MXPA01001847A - Arylpiperazines and their use as metalloproteinase inhibiting agents (mmp). - Google Patents

Arylpiperazines and their use as metalloproteinase inhibiting agents (mmp).

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MXPA01001847A
MXPA01001847A MXPA01001847A MXPA01001847A MXPA01001847A MX PA01001847 A MXPA01001847 A MX PA01001847A MX PA01001847 A MXPA01001847 A MX PA01001847A MX PA01001847 A MXPA01001847 A MX PA01001847A MX PA01001847 A MXPA01001847 A MX PA01001847A
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pharmaceutically acceptable
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MXPA01001847A
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Bernard Christophe Barlaam
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Astrazeneca Ab
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Abstract

Arylpiperazines of formula (I) useful as metalloproteinase inhibitors, especially as inhibitors of MMP 13.

Description

ARILPIPERAZINES AND THEIR USE AS INHIBITORS FOR INHIBITING -METAIOPOPETINASE (MMP) DESCRIPTION OF THE INVENTION The present invention relates to compounds useful in the inhibition of metalloproteinases and in particular to pharmaceutical compositions comprising them, as well as to their use. The compounds of this invention are inhibitors of one or more metalloproteinase enzymes. Metalloproteinases are a superfamily of proteinases (enzymes) whose numbers in recent years have increased dramatically. Based on structural and functional considerations these enzymes have been classified within families and subfamilies as described in N. M. Hooper (1994) FEBS Letters 354: 1-6. Examples of metalloproteinases include the metalloproteinase matrix (MMP) such as collagenases (MMP1, MMP8, MMP13), gelatinases (MMP2, MMP9), stromelysins (MMP3, MMP10, MMP11), matrilysin (MMP7), metalloeslastase (MMP12); enamelisin (MMP19), and MT-MMP (MMP14, MMP15, MMP16, MMP17); retrolisin or adamalysin or MDC family that includes secretases and sedase enzymes that convert TNF (ADAM10 and TACE); the astazin family that includes enzymes such as prokinase-processing proteinase (PCP); and other metalloprotenases such as aggrecanase, the enzyme family that converts endothelin and the enzyme family that converts angiotensin. Metalloproteinases are believed to be important in plethora or physiological disease processes involving tissue remodeling such as embryonic development, bone formation and uterine remodeling during menstruation. This is based on the ability of metalloproteinases to unfold a wide range of matrix substrates such as collagen, proteoglycan and fibronectin. Metalloproteinases are also believed to be important in the processing, or secretion, of important biological cell mediators, such as tumor necrosis factors (TNF); and the processing of subsequent translation proteolysis, or shedding, of biologically important membrane proteins, such as the low affinity of the CD23 IgE receptor (for a more complete list see NM Hooper et al., (1997) Biochem J. 321: 265 -279). Metalloproteinases have been associated with many disease conditions. Inhibition of the activity of one or more metalloproteinases may well be of benefit in these disease conditions, for example: various inflammatory and allergic diseases "such as, inflammation of the joint (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the tract Gastrointestinal (especially inflammatory bowel disease, ulcerative colitis and gastritis), skin inflammation (especially psoriasis, eczema, dermatitis), in tumor metastasis or invasion, in disease associated with uncontrolled degradation of the extracellular matrix such as osteoarthritis; bone resorption disease (such as osteoporosis and Paget's disease), in diseases associated with aberrant angiogenesis, improved collagen remodeling associated with diabetes, periodontal disease (such as gingivitis), corneal ulceration, skin ulceration, conditions post-operative (such as colonic anastomosis) and cure dermal wound ion; demyelinating diseases of the central and peripheral nervous systems (such as multiple sclerosis); Alzheimer disease; and extracellular matrix remodeling observed in cardiovascular diseases such as restenosis and atherosclerosis. A number of metalloproteinase inhibitors are known; Different classes of compounds may have different degrees of potency and selectivity to inhibit several metalloproteinases. A new class of compounds that are inhibitors of metalloproteinases have been discovered and are of particular interest in inhibiting MMP-13, as well as MMP-9. The compounds of this invention have beneficial potency and / or pharmacokinetic properties. The MMP13, or collagenase 3, was initially cloned from the cDNA library derived from the breast tumor [J. M. P. Freije et al. (1994) Journal of Biological Chemistry 269 (24): 16766-16773]. PCR-RNA analysis of RNAs from a wide range of tissues indicated that MMP13 expression was limited to breast carcinomas when it was not found in breast fibroadenomas, normal or latent mammary glands, placenta, liver, ovary, uterus, prostate or parotid glandura or in breast cancer cell lines (T47-D, MCF-7 and ZR75-1). Subsequent to this observation MMP13 has been detected in the transformation of epidermal eratinocytes [N. Johansson et al. , (1997) Cell Growth Differ. 8 (2): 243-250], squamous cell carcinomas [N. Johansson et al. , (1997) Am. J. Pathol. 151 (2): 99-508] and epidermal tumors [K. Airóla et al. , (1997) J. Invest. Dermatol. 109 (2) -. 225-231]. These results suggest that MMP13 is secreted by transformed epithelial cells and can be involved in the degradation of extracellular matrix and cell matrix interaction associated with metastasis, especially as observed in breast cancer lesions and growth of malignant epithelium in skin carcinogenesis . Recent published data imply that MMP13 plays a role in the movement of other connective tissues. For example, consistent with the specificity and preference of the MMP13 substrate for type II collagen degradation [P. G. Mitchell et al. , (1996) J. Clin. Invest. 97 (3): 761-768; V. Knauper et al. , (1996) The Biochemical Journal 271: 1544-1550], MMP13 has been hypothesized to serve a role during primary ossification and skeletal remodeling [M. Stahe-Backdahl et al. (1997) Lab. Invest. 76 (5): 717-728; N. Johansson et al. , (1997) Dev. Dyn. 208 (3): 387-397], in destructive joint disease such as rheumatoid arthritis and osteoarthritis [D. enicke et al. (1996) J. Rheu atol. 23: 590-595; P. G. Mitchell et al., (1996) J. Clin. Invest. 97 (3): 761-768; O. Lindy et al. (1997) Arthritis Rheum 40 (8): 1391-1399], and during the aseptic softening of hip replacements ([S. Imai et al., (1998) J. Bone Joint Surg. Br. 80 (4): 701 -710] MMP13 has also been implicated in chronic adult periodontitis as it has been localized to epithelium of human gingival tissue of chronically inflamed mucosa [VJ Uitto et al., (1998) Am. J. Pathol 152 (6): 1489 -1499] and in the remodeling of the collagen matrix in chronic wounds [M. Vaalamo et al., (1997) J. Invest. Dermatol. 109 (1): 96-101]. MMP9 (Gelatinase B; 92kDa Collagenase Type IV; Gelatinase 92kDa) is a secreted protein which is first purified, then cloned and sequenced, in 1989 (S.M.
Wilhelm et al (1989) J. Biol Chem. 264 (29): 17213-17221.
Errata published in J. Biol. Chem. (1990) 265 (36): 22570).
A recent review of MMP9 provides an excellent source for detailed information and references on this protease: T.H. Vu & Z Werb (1998) (In: Matrix Metalloproteinases, 1998. Edited by W. C. Parks &R.P. Mecham, Ppll5-148, Academic Press, ISBN 0-12-545090-7). The following points are indicated from the review by T. H. Vu & Z. Werb (1998). MMP9 expression is usually limited to a few cell types, including trophoblasts, osteoclasts, neutrophils and macrophages. However, their expression can be induced in these same cells and in other cell types by various mediators, including exposure of the cells to growth factors or cytokines. These are the same mediators often involved in the initiation of an inflammatory response. As with other MMPs, secreted MMP9 are released as an inactive Pro enzyme that is subsequently cleaved to form the enzymatically active enzyme. The proteases required for this activation in vivo are not known. The rest of the active MMP9 against the inactive enzyme is further regulated in vivo by interaction with TIMP-1 (Metalloproteinase-1 tissue inhibitor), a naturally occurring protein. TIMP-1 binds to the C-terminal region of MMP9, leading to "the inhibition of the catalytic domain of MMP9." The rest of induced expression of ProMMP9, unfolding of Pro to the active MMP9 and the presence of TIMP-1 combined to determine the amount of catalytically active MMP9 which is present at a local site Proteolytically active MMP9 attacks substrates including gelatin, elastin, and native Type IV and Type V collagens, without activity against native Type I collagen, proteoglycans or laminins. a body of growth data involving roles for MMP9 in various physiological and pathological processes.Physiological roles include the invasion of embryonic trophoblasts through the uterine epithelium in the early stages of embryonic implantation, some role in the growth and development of bones and migration of inflammatory cells from the vasculature in tissues.The expression of increased MMP9 was observed or in certain pathological conditions, so that MMP9 implies in the disease process such as arthritis, tumor metastasis, Alzheimer's, Multiple Sclerosis and plaque rupture in atherosclerosis leading to acute coronary conditions, such as Myocardial Infarction. In a first aspect of the invention, compounds of the formula I are provided wherein ring B is a monocyclic or bicyclic, aryl, aralkyl, heteroaryl or heteroaralkyl ring, comprising up to 12 ring atoms and containing one or more heteroatoms independently chosen from N, 0 and S; alternatively ring B can be Joyphenyl; ring B can optionally be linked to ring A by an alkyl chain of Cl-4 or of alkoxy of Cl-4 linking the position 2 of ring B with an atom of carbon alpha to X2; each R3 independently is selected from hydrogen, halogen, N02, COOR wherein R is hydrogen or Cl-6 alkyl, CN, CF3, Cl-6 alkyl, -S-Cl-6 alkyl, -SO alkyl -Cl-β, alkyl of -S02-C1-6, alkoxy of Cl-6 and up to CIO aryloxy, n is 1, 2 or 3; P is - (CH2) n- where n = 0, 1, 2 or P is a chain of alkene or alkyne of up to six carbon atoms; where X2 s C, P can be -Het-, - (CH [R6]) n-Het-, -Het- (CH [R6] n- or -Het- (CH [R6] n-Het-, in where Het is selected from -CO-, -S-, SO-, -S02-, -NR6-, or -O- where n is 1 or 2, or P can be selected from -CO-N (R6) - N (R6) -CO-, -S02-N (R6) - and -N (R6) -S02-, and R6 is hydrogen, Cl-6 alkyl, up to C10 aralkyl or up to heteroalkyl of C9; Ring A is a 5-7 membered aliphatic ring and may optionally be mono- or di-substituted by optionally substituted Cl-6 alkyl or Cl-6 alkoxy, each substituent being independently selected from halogen, alkyl of Cl-6 or an oxo group; XI and X2 are independently selected from N and C, wherein a ring substituent or ring A is an oxo group that is preferably adjacent to a ring of nitrogen atom; And it is selected from -S02- and -C0-; Z is -CONHOH, Y is -CO- and Q is selected from -C (R6) (R7) -, -C (R6) (-R7) -CH2-, N (R6) -, and -N ( R6) -CH2- wherein R6 is as defined above, and only in relation to Q as defined herein, R6 may also represent up to one CIO aryl and up to a C9 heteroaryl, and R7 is H, alkyl Cl-6, or together with R6 forms a ring of 5, 6 or 7 spiro carbocyclic or heterocyclic members, the latter contains at least one heteroatom selected from N, O and S; Z is -CONHOH, Y is -S02- and Q is selected from -C. { R6) (R7) - and -C (R6) (R7) -CH2-; or Z is -N (OH) CHO and Q is selected from -CH (R6) -, -CH (R6) -CH2- and -N (R6) -CH2-, R1 is H, Cl-6 alkyl , C5-7 cycloalkyl, up to CIO aryl, up to CIO heteroaryl, to C12 aralkyl, or up to C12 heteroarylalkyl, all optionally substituted by up to three groups independently selected from N02, CF3, halogen, Cl-4 alkyl, carboxylalkyl (Cl-4), up to C6 cycloalkyl, -0R4, -SR4, Cl-4 alkyl substituted with -0R4, -SR4 (and its oxidized analogs), NR, or NY-R4, or Cl- alkyl 4-Y-NR $, with the proviso that when R1 is -OH, -OR4, -SR4, or NR4 or NY-R4 then Z is not -N (OH) CO, or R1 is 2.3.4, 5,6-pentafluorophenyl; R4 is hydrogen, Cl-6 alkyl, up to CIO or up to CIO heteroaryl or up to C9 aralkyl, each optionally independently substituted by halogen, N02, CN, CF3, Cl-6 alkyl, -S- Cl-6 alkyl, -SO-C1- alkyl 6, S02-C1-6 alkyl or Cl-6 alkoxy; R 2 is H, Cl-6 alkyl, or together with R 1 forms a ring of 5, 6 or 7 spiro carboxylic or heterocyclic members, the latter containing at least one heteroatom selected from N, O, and S; also the group Q can be linked either Rl or R2 to form a ring of 5, 6, or 7 alkyl or heteroalkyl members, comprising one or more of O, S and N. Any alkyl groups noted above can be chain linear or branched. Convenient values for the above groups include the following: a ring A = a 5-6 membered aliphatic ring, and may optionally be mono- or di-substituted by optionally substituted Cl-6 alkyl or Cl-6 alkoxy, each substituent being independently selected from halogen, Cl-6 alkyl or an oxo group; R3 = hydrogen, halogen, N02, CF3, alkyl of Cl-4, and alkoxy of Cl-4, n is 1 or 2 such as individually 4-fluoro, CF3, 4-chloro and 3,4-dichloro; The ring B = monocyclic or bicyclic aryl, aralkyl or heteroaryl having up to 10 ring atoms, especially monocyclic, aralkyl or heteroaryl aryl having up to 7 ring atoms, more especially monocyclic or heteroaryl aryl having up to 6 atoms in the ring ring, such as a phenyl or pyridyl ring; P = - (CH2) n- where n is 0 or 1, or -O-, or -CO-N (R6) -; One or both of X2 and XI = N, or XI is N, or X2 is C; Y = -S02-, Y = -CO-; Q = -CH (R6) -, -CH (R6) -CH2-, and -N (R6) -CH2- where R6 is hydrogen or Cl-6 alkyl, also wherein Q is linked to R1 or R2 to form a C5-7 alkyl or heteroalkyl ring such as a cyclohexyl ring; R1 = hydrogen, Cl-6 alkyl, C5-7 cycloalkyl, up to C12 aralkyl, up to C12 heteroarylalkyl, up to CIO aryl, or heteroaryl such as to C6 aryl; all optionally substituted by up to three halogen atoms, or by CF3; R 2 = hydrogen, or together with R 1 represent a ring of 5 or 6 spiro carbocyclic or heterocyclic members, such as a tetrahydropyran ring; R4 = up to CIO aryl optionally substituted by halogen, N02, CN, CF3, Cl-6 alkyl, -S-Cl-6 alkyl, -SO-Cl-6 alkyl, -S02-Cl-6 alkyl or alkoxy of Cl-6; Z = -CONHOH-, Z = -N (OH) CHO. Preferred values for the above groups include the following: R3 = hydrogen, halogen such as chlorine, bromine or fluorine, N02, CF3, methyl, ethyl, methoxy, ethoxy, particularly methoxy or fluorine; The ring B = a monocyclic, aralkyl or heteroaryl aryl ring having up to 7 ring atoms, such as phenyl, biphenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazolinyl, especially phenyl, pyridyl and pyrimidyl, more especially phenyl, 2- pyridyl and 2,4-pyrimidyl; P = a direct link; both X2 and XI are N; Y = S02-; 'Q = * - CH2-; R 1 is phenyl, 4-trifluoromethylphenyl, phenethyl, phenethyl, isobutyl, cyclopentyl, benzyloxymethyl, 3,4-dichlorophenyl, pyridyl, pyridylethyl, thiophenylpropyl, bromothiophenyl, pyrimidinethyl, pyrimidinylpropyl, pyridylethyl, pyridylpropyl or together with R 2 is spirocyclohexane or spiro-4- piran; R2 is hydrogen Z = -N (OH) CHO Most preferred values include R3 which is halogen, the substituent is preferably meta or para to the ring linkage where ring B is an aryl or heteroaryl ring, wherein ring B is phenyl, then especially 4-fluoro and wherein ring B is pyridyl, then 3-, or 4-chloro (as appropriate); Q = -CH2-. Preferred combinations of Rings B and A include phenyl and piperazinyl; pyridyl and piperazinyl, and pyrimidine and piperazinyl respectively. Particular alicyclics, fused and heterocyclic rings for ring B include any of: The particular rings for ring A include any of: and its seven corresponding analogous members. It will be appreciated that particular substituents and numbers of substituents on rings A and B are selected so as to avoid spherically undesirable combinations. This also applies to rings as can be formed by Rl and Q, R2 and Q as well as R6 and R7. When optically active centers exist in the compounds of formula I, all individual optically active forms and combinations thereof are described as specific individual embodiments of the invention, as well as their corresponding racemates. Specific compounds include M / Z M + l (ESP +) 438 M / Z M + l (ESP +) 487 M / Z M + I (ESP +) 454 M / Z M + l (ESP +) 420 MZM + 1 (ESP +) 451 MZ M + l (ESP +) 438 MZ M + I (ESP + -) 496 M / ZM + 1 (ESP +) 471 M / Z M + l (ESP +) 528 M / Z + I (ESP +) 511 M / Z M + l (ESP +) 470 M / Z M + l (ESP +) 495 MZ M + l (ESP +) 495 M / Z M + l (ESP +) 468 M / ZM + l (ESP +) 455 M / Z M + l (ESP +) 456 wherein R = phenyl or phenethyl and wherein R = isobutyl or a spiro-4-pyran ring As previously noted, the compounds of the invention are metalloproteinase inhibitors, in particular they are inhibitors of MMP13. Each of the above indications for the compounds of formula I represents a separate and particular embodiment of the invention. While not wishing to be bound by theoretical considerations, the compounds of the invention are believed to show selective inhibition for any of the foregoing indications in relation to any MMP1 inhibitory activity, as a non-limiting example fold selectivity of 100 may be shown. -1000 during any inhibitory activity of MMP1. It has further been found that compounds of formula 1 wherein ring B is a phenyl, pyridyl ring (such as 2-pyridyl or 3-pyridyl, especially 2-pyridyl) optionally mono- or di-substituted, preferably mono-substituted, by halogen (for example, chlorine), P is a direct bond; ring A is a piperazinyl or piperidinyl ring. Y is -S02- and Q is alkylene of Cl-4 (for example -CH2-), especially -CH2-, R1 is as defined by Formula 1 and is especially 2-phenylpropyl, 2- (2-pyridyl) propyl , 2- (3-pyridyl) propyl, 2- (4-pyridyl) propyl, phenyl, benzyloxymethyl, 4-phenylbutyl, 2-phenylbutyl, or 2- (2-thienyl) propyl; and Z is -N (OH) CHO; they are of particular use as aggrecanase inhibitors, ie, aggrecan degradation inhibitors. Of particular observation are the compounds of formula I wherein ring B is a phenyl ring, 3-methylphenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, or 3,4-dichlorophenyl or 5-chloro-2-pyridyl; P is a direct bond, ring A is a piperidinyl or piperazinyl especially piperazinyl, Y is S02, Q is -CH2-, Z is - (OH) CHO and R1 is phenyl, phenybutylene, pheneopropylene, 2-pyridylethylene, 2-pyridylisopropylene , 3-pyridylisopropylene, 4-pyridylisopropylene, or 4-chlorophenyloxydimethylmethylene. Also of note are compounds of formula I wherein ring B is phenyl monosubstituted by chlorine or fluorine, especially 4-chlorophenyl and 4-phlorophenyl; P is a direct link; ring A is piperidinyl, Y is S02, Q is -CH2-, Z is -CONHOH and R1 is hydrogen, i-butyl or spiro-tetrahydropyranyl. Particular compounds include BAYQ R1 z 4-F-Ph PIP SO2 CH2 CH2CH (CH3) P RH 4-F-Ph PIP SO2 CH2 PhCH2CH2CH2CH2 RH 3-CI-Ph PIP S02 CH2 PhCH20CH2 RH 4-F-Ph PIP SO2 CH2 4-PyridylCH3 ) CH2 RH 4-F-Ph Piperidinyl SO2 CH2 PhCH (CH3) CH2 RH 4-F-Ph PIP S02 CH2 (R) -2-PhCH (CH3) CH2 RH 3-Cl-Ph PIP SO2 CH2 3-PyriddICH (CH3) CH2 RH 3-CH3-P PIP SO2 CH2 Ph RH 4-F-Ph PIP S02 CH2 CH2CH (CH2CH3) Ph RH 5-Cl-2-Pyridyl PIP SO2 CH2 3-PyridylCH (CH3) CH2 RH 4-FP PIP S02 CH2 2-t¡? PhenylCH (CH3) CH2 RH 4-F-Ph PIP SO2 CH2 2-CH3P CH2CH2 RH 4-F-Ph Piperidinyl SO2 CH2 3-PyridCH (CH3) CH2 RH 4-Br-P PIP S02 CH2 PhCH (CH3) CH2 RH 4-F-Ph PIP SO2 CH2 4-F-PhCH (CH3) CH2 RH 4-F-Ph PIP SO2 CH2 2-PirazilCH (CH3) CH2 RH wherein PIP = piperazinyl RH = reverse hydroxamate group and R2 = hydrogen The compounds of the invention can be provided as pharmaceutically acceptable salts. These include acid addition salts, such as hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulfuric acid. In another aspect suitable salts are base salts such as an alkali metal salt, for example, sodium or potassium, an alkaline earth metal salt, for example, calcium, or magnesium or organic amine salt for example, triethylamine. Hydrolyzable esters can also be provided in vivo. These are pharmaceutically acceptable esters that hydrolyze in the human body to produce the parent compound. Such esters can be identified by administration, for example, intravenously to a test animal, the compound under test and subsequently examining the fluids of the animal's test body. Suitable hydrolysable esters in vivo for carboxy include methoxymethyl and for hydroxy include formyl and acetyl, especially acetyl. To use a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for therapeutic treatment (including prophylactic treatment) or mammals' including humans, it is normally formulated in accordance with standard pharmaceutical practice as a composition pharmaceutical Therefore in another aspect the present invention provides a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester and pharmaceutically acceptable carrier. The pharmaceutical compositions of this invention can be administered in standard form for the disease condition that is desired to be treated, for example, by oral, local, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation. For these purposes the compounds of this invention can be formulated by means known in the art in the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, powders. finally divided or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions. In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or may be co-administered (simultaneously or sequentially) with one or more pharmacological agents of value in treating one or more disease conditions mentioned herein in the above. The pharmaceutical compositions of this invention will normally be administered to humans, so that, for example, a daily dose of 0.5 to 75 mg / kg of body weight (and preferably 0.5 to 30 mg / kg of body weight) is received. This daily dose can be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and in the particular disease condition being treated according to the known principles in the technique. Typically dosage unit forms will contain about 1 mg to 500 mg of a compound of this invention. Therefore in a further aspect, the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for use in a method of therapeutic treatment of human or animal body. In still a further aspect of the present invention provides a method for treating a metalloproteinase-mediated disease condition comprising administering to a warm-blooded animal a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or hydrolysable ester in vivo thereof. In another aspect the present invention provides a process for preparing a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof which process comprises a) reacting a compound of the formula (II) or a pharmaceutically salt acceptable or in vivo hydrolysable ester thereof with a compound of the formula (III) wherein Xi represents X or a precursor of X (either by modification or displacement) or an activated form of X suitable for reaction with Yx; Yi represents Y, a precursor of Y, or an activated form of Y suitable for reaction with X? I7 by way of non-limiting example, when X is C, then Xi can be derived to include a Y precursor for reaction with a compound of formula III wherein Y1 is a precursor of Y; Zr represents a protected form of Z, a precursor of Z (either by modification or displacement of Z1) or an activated form of Z; And where Q = - (CH2) (R6) - then reacting a compound of the formula IX with an appropriate compound of the formula R1-CO-R2 to produce an alkene of the formula X, which is then converted to a compound of formula XI wherein Z * is a hydroxylamine precursor of group Z, and then convert Z * to group Z, all as stated below: b) reacting a compound of the formula (IV)) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof with a compound of the formula (V) wherein B1 represents a suitable ring function or a substituent group for the reaction with P1; Z1 is as defined herein in the foregoing; and P1 represents a suitably activated form of linkage P for reaction with B1 0 where X2 = N then Pl may be present in ring A in place of ring B or, as required, linker P may be formed by the appropriate reaction of the precursor groups P "and P" 'provided in rings B1 and A respectively, or vice versa. A compound of the formula (II) is conveniently prepared by reacting a compound of the formula (VI) with a compound of the formula (VII) wherein B1 represents a suitable ring function or a substituent group, X21 represents X or a precursor of X (either by modification or displacement) or an activated form of X suitable for the reaction with B1 or wherein B1 and X2r when they react together they provide the linker P between: ring A and ring B in the compounds of formula (II). By way of non-limiting example, when X2 is N then ring B is suitably derived to introduce linker P through B1, and when X2 is C then both ring B and ring A are suitably derived to provide linker P for the reaction of B1 and X2Z. It will be appreciated that many of the relevant starting materials are commercially available. In addition the following tables show details of aldehyde intermediates and their corresponding registration numbers in Chemical Excerpts.
Aldehydes without Humors of Record of Chemical Extracts 3- (2-pyrimidyl) propionaldehyde. To a solution of 2-Bromopyrimidine (7.95 g, 0.05 M) in acetonitrile (150 mL) was added propargyl alcohol (4.2 g, 0.075 M), bis- (triphenylphosphine) -palladium (II) chloride (750 mg, 1 mm ), copper iodide (100 mg, 0.5 mM) and triethylamine (25 mL, 0.25 M) and the mixture was stirred and heated at 70 ° C for 2 hours. An additional amount of propargyl alcohol (2.1 g, 0.038 M) bis- (triphenylphosphine) -palladium (II) chloride (375 mg, 0.5 mil), and copper iodide (50 mg, 0.25 mil) was then added to the mixture of reaction that was stirred and heated to 70 ° C for an additional 1 hour. The reaction mixture was evaporated to dryness and the residue which was pre-absorbed on silica was chromatographed. Elution with ethyl acetate gave 3- (2-pyrimidyl) prop-2-yn-3-ol as a yellow solid 4.45 g (66%). NMR (CDC13) 2.9 (1H, t), 4.5 (2H, d), 7.3 (1H, d), 8.8 (2H, t), MS Found MH + 135 3- (2-pyrimidyl) prop-2-in was dissolved -l-ol (4.45 g, 0.033 M) in ethyl acetate (140 ml), 10% Pd / C (890 mg) was added and the mixture was stirred under a hydrogen atmosphere for 6 hours. The reaction mixture was filtered through Celite and the filtrate was evaporated to give 3- (2-pyrimidyl) propan-1-ol as a yellow oil, 4.15 g (91%). NMR (CDCl 3) 2.1 (2H, m), 3.2 (2H, t) 3.8 (2H, t), 7.2 (1H; t) 8.7 (2H, d) * MS Found MH + 139. 3- (2-pyrimidyl) was oxidized ) propan-1-ol to give 3- (2-pyrimidyl) propionaldehyde as a yellow oil NMR (CDC13) 3.0 (2H, t), 3.4 (2H, t), 7.1 (1H, t), 8.7 (2H, d), 9.9 (1H, s) using the Swern oxidation described in this patent. Using the procedure described above, the following 4- (2-pyrimidyl) butyraldehyde aldehydes were prepared using 3-butin-1-ol instead of propargyl alcohol. NMR CDC13 9.8 (1H, s), 8.6 (2H, m), 7.15 (1H, m), 3.0 (2H, m), 2.5 (2H, m), 2.2 (2H, m). 4- (5-pyrimidyl) butyraldehyde using 3-butin-l-ol instead of propargyl alcohol and 5-bromopyrimidine instead of 2-bromopyrimidine NMR CDC13 9.8 (1H, s), 9.1 (1H, s) 8.6 (2h, s), 2.7 (2H, t), 2.55 (2H, t), 2.0 (2H, m). 4- (2-pyridyl) butyraldehyde using 3-butin-1-ol instead of propargyl alcohol and 2-bromopyridine instead of 2-bromopyrimidine NMR CDC13 9.8 (1H, s), 8.6 (1H, d), 7.6 (1H , m); 7.1 (2H, m); 2.8 (2H, t); 2.55 (2H, t), 2.0 (2H, m). The compounds of this invention can be evaluated for example in the following assays: Isolated Enzyme Assays The Matrix Metalloproteinase family includes for example MMP13.
Recombinant human proMMP13 can be expressed and purified as described by Knauper et al. [V. Knauper et al. , (nineteen ninety six). The Biochemical Journal 271: 1544-1550 (1996)]. The purified enzyme can be used to check activity inhibitors as follows: purified proMMPl3 is activated using aminophenylmercuric acid lmM (APMA), 20 hours at 21 ° C, activated MMP13 (11.25 ng per assay) was incubated for 4-5 hours at 35 ° C in assay buffer (0.1 M Tris-HCl, pH 7.5, containing 0. IMM NaCl, 20 mM CaCl 2, 0.02 mM ZnCl and 0.05% (w / v) Brij 35 using the synthetic substrate of 7 -methoxycoumarin-4-yl) acetyl. Pro. Leu Gly. Leu. N-3- (2,4-dinitrophenyl) -L-2, 3-diaminopropionyl. To . rg. NH2 in the presence or absence of inhibitors. The activity is determined by measuring the fluorescence at? Ex 328 nm and? Em 393 nm. Percent inhibition was calculated as follows:% Inhibition is equal to the [Inferior Fluorescence - Ancestor Florescence] divided by the [Inferior Fluorescence - Inferior Fluorescence] • Similar protocols can be used by other MMPs expressed and purified using optimal substrate conditions and buffers for the particular MMP, for example, as described in C. Graham Knight et al. , (1992) FEBS Lett. 296 (3): 263-266. Adamalisine family including, for example, TNF convertase The ability of the compounds to inhibit the proton NFase convertase enzyme can be evaluated using an isolated, partially purified enzyme assay, the enzyme being obtained from the THP-1 membranes as described by KM Mohler et al. , (1994) Nature 3_70: 218-220. Purified enzyme activity and inhibition thereof was determined by incubating the partially purified enzyme in the presence or absence of the test compounds using the substrate 4 ', 5' -Dimethoxy-fluoresceinyl Ser. Pro. Leu. To. Gln.Ala. Val. Arg. Be . Be . Be . Arg. Cys (4- (3-succinimid-1-yl) -fluorescein) -NH2 in assay buffer (50 mM Tris HCl, pH 7.4 containing 0.1% (w / v) Triton X-100 and 2mM CaCl2) at 26 ° C for 18 hours. The amount of inhibition is determined as for MMP13, except that? Ex 490 nm and? Em 530nm were used. The substrate was synthesized as follows. The peptide part of the substrate was assembled in Fmoc-NH-Rink-MBHA-polystyrene resin either manually or in an automatic peptide synthesizer through standard methods involving the use of amino acids Fmoc and O-benzotriazole-1-hexafluorophosphate il-N, N, N ', N' -tetramethyluronium (HBTU) as a coupling agent with at least an excess of 4 or 5 amino acid folds Fmoc and HBTU. Ser1 and Pro2 were doubled. The following side chain protection was used strategically; Ser1 (But) / Gln5 (Trityl), Arg8'12 (Pmc or Pbf), Ser9'10'11 (Trityl), Cys13 (Trityl). Following the assembly, the N-terminal Fmoc protection group was removed by treating the Fmoc peptidyl resin with DMF. The aminopeptidyl resin thus obtained was acylated by treatment of 1.5-2 hours at 70 ° C with 1.5-2 equivalents of 4 ', 5'-dimethoxy-fluorescein-4 (5) -carboxylic acid [Khanna &; Ullman, (1980) Anal Biochem. 108: 156-161 which has been pre-activated with diisopropylcarbodiimide and 1-hydroxybenzotriazole in DMF]. The dimethoxyfluoresceinyl peptide was then simultaneously deprotected and split from the resin by treatment with trfluoroacetic acid containing 5% each of water and triethylsilane. The dimethoxyfluoresceinyl peptide was isolated by evaporation, trituration with diethyl ether and filtration. The isolated peptide was reacted with 4- (N-maleimido) -fluorescein in DMF containing diisopropylethylamine, the product purified by RP-HPLC and finally isolated by freeze-drying from aqueous acetic acid. The product was characterized by MALDI-TOF EM and amino acid analysis. Natural Substrates The activity of the compounds of the invention as inhibitors of aggrecan degradation can be evaluated using methods for example based on the descriptions of E.C. Arner et al. , (1998) Osteoarthritis and Cartilage jS: 214-228; (1999) Journal of Biological Chemistry, 274 (10), 6594-6601 and the antibodies described herein. The potency of the compounds to act as inhibitors against collagenases can be determined as described by T. Cawston and A. Barrett (1979) Anal. Biochem. 99: 340-345. Inhibition of metalloproteinase activity in cell / tissue-based activity Test as an agent to inhibit membrane effusions such as TNF convertase The ability of the compounds of this invention to inhibit cellular processing of TNFa production can be evaluated in THP- cells. 1 using an ELISA to detect the release of TNF essentially as described K. M.'Mohler et al. , (1994) Nature 370: 218-220. In a similar manner the processing or spillage of other membrane molecules such as those described in N. M. Hooper et al. , (1997) Biochem. J. 321: 265-279 can be tested using appropriate cell lines and with suitable antibodies to detect the separation protein. Test as an agent to inhibit cell-based invasion The ability of the compound of this invention to inhibit the migration of cells in an invasion assay can be determined as described in A. Albini et al. , (1987) Cancer Research 47: 3239-3245. Test as an agent to inhibit TNF shedding activity in whole blood The ability of the compounds of this invention to inhibit TNFa production is evaluated in human whole blood assays where LPS is used to stimulate the release of TNFa. Heparinized human blood (10 Units / ml) obtained from volunteers is diluted 1: 5 with a medium (RPMI1640 + bicarbonate, penicillin, streptomycin and glutamine) and incubated (160 μl), with 20 μl of the test compound (triplicates ), in DMSO or appropriate vehicle, for 30 minutes at 37 ° C in a humidified incubator (5% C02 / 95% air), before the addition of 20 μl of LPS (E. coli, 0111: B4; final 10 μg / ml). Each assay includes controls of diluted blood incubated with a medium alone (6 wells / plate) or an inhibitor of TNFa known as standard. The plates were then incubated for 6 hours at 37 ° C (humidified incubator), centrifuged (2000 rpm for 10 minutes; 4 ° C), harvested plasma (50-100 μl) and stored in 96 well plates at -70 ° C before the subsequent analysis for TNFa concentration by ELISA. Test as an agent to inhibit in vitro cartilage degradation The ability of the compounds of this invention to inhibit the degradation of the aggrecan or cartilage collagen components can be evaluated essentially as described by K. M. Bottomley et al. (1997) Biochem J. 323: 483-488. Pharmacodynamic test A pharmacodynamic test ex vivo using the synthetic substrate assays above or alternatively HPLC or mass spectrometric analysis is used to evaluate the cleaning properties and bioavailability of the compounds of this invention. This is a generic test that can be used to estimate the rate of cleanliness of compounds across a range of species. The animals (e.g., rats, marmosets) were dosed iv or po with a soluble formulation of the compound (such as 20% w / v DMSO, 60% w / v PEG400) and at subsequent time points (by example, 5, 15, 30, 60, 120, 240, 480, 720, 1220 minutes) the blood samples were taken from an appropriate container in heparin 10U. Plasma fractions were obtained following centrifugation and plasma proteins precipitated with acetonitrile (80% w / v final concentration). After 30 minutes at -20 ° C the plasma proteins were pelleted by centrifugation and the supernatant fraction was evaporated to dryness using a Savant speed vac. The pellet is reconstituted in assay buffer and subsequently analyzed for compound content using the synthetic substrate assay. Briefly, a concentration-response curve of the compound was constructed for the evaluation of the underlying compound. Serious dilutions of the reconstituted plasma extracts were evaluated by activity and the amount of the compound present in the original plasma sample was calculated using the response-concentration curve taking into account the total plasma dilution factor. In vivo assessments Test as an anti-TNF agent The ability of the compounds of this invention as ex vivo TNFa inhibitors was evaluated in the rat. Briefly, groups of male Wistar Alderley Park (AP) rats (180-210 g) were dosed with the compound (6 rats) or drug vehicle (10 rats) by the appropriate route, for example peroral (po), intraperitoneal (ip) subcutaneous (s.c.) Ninety minutes later, the rats were sacrificed using a high concentration of CO 2 and bleeding through the posterior vena cava in 5 units of sodium heparin / ml of blood. The blood samples were immediately placed on ice and centrifuged at 2000 rpm for 10 minutes at 4 ° C and the harvested plasmas were frozen at -20 ° C for subsequent testing of their effect on the production of TNFa by human blood stimulated by LPS. . The rat plasma samples were thawed and 175 μl of each sample was added to a paternal format set in a 96U well plate. Fifty μl of heparinized human blood was then added to each well, mixed and the plate incubated for 30 minutes at 37 ° C (humidified incubator). LPS (25 μl, final concentration, 10 μg / ml) was added to the wells and incubation continued for an additional 5.5 hours. The control wells were incubated with 25 μl of a medium alone. The plates were then centrifuged for 10 minutes at 2000 rpm and 200 μl of the supernatants were transferred to a 96-well plate and frozen at -20 ° C for subsequent analysis of TNF concentration for ELISA. Data analysis for dedicated software calculations for each compound / dose: Percent TNFa inhibition = TNFa Medium (Controls) - TNFa Medium (Treated) X 100 TNFa Medium (Controls) Test as an anti-arthritic agent The activity of A compound such as an anti-arthritic is proven in collagen-induced arthritis (CIA) as defined by DE Trentham et al., (1977) J. Exp. Med. 146,: 857. In this collagen of type II soluble native acid model causes polyarthritis in rats when administered in incomplete Freunds adjuvant. Similar conditions can be used to induce arthritis in mice and primates. Test as an anti-cancer agent The activity of a compound as an anti-cancer agent can be evaluated essentially as described in IJ Fidler (1978) Methods in Cancer Research 15: 399-439, using for example the B16 cell line (described in B. Hibner et al., Extract 283 p75 lOth NCI-EORT Symposium, Amsterdam June 16-19 1998). The invention will now be illustrated, but not limited by the following Examples: EXAMPLES Example 1 1- [2- (N-formyl-N-hydroxyamino) -2-phenylethanesulfonyl] -4- (4-fluorophenyl) piperazine To a solution of 1- [2- (hydroxyamino) -2-phenylethanesulfonyl] -4- (4-fluorophenyl) piperazine (338 mg, 0.89 mmol) in THF (5 ml) and formic acid (2 ml) was added a mixture formed previously of formic acid (2 ml) and acetic anhydride (0.5 ml). The mixture was stirred at room temperature for one hour. The mixture was evaporated in vacuo and toluene (2 x 5 ml) was added and evaporated in vacuo. The residue was taken up in CH2Cl2-methanol (6 mL, 9: 1) and silica (1 g) was added. The mixture was stirred for 18 hours. The silica was filtered and rinsed with CH2Cl2-methanol (9: 1). The residue was purified on silica gel (eluent: CH 2 Cl 2 -MeOH 4%) to give the title compound as a slightly orange solid (220 mg, 61%).
XN NMR (CDCl 3): 8.45 and 8.15 (s, 1H), 7.39 (m, 5H), 6.97 (m, 2H), 6.88 (m, 2H), 5.89 and 5.35 (m, 1H), 4.05 and 3.85 (m , 1H), 3.30-3.53 (m, 5H), 3.20-3.10 (m, 4H); MS (ESI): 408 (MH +), 430 (MNa +); EA: calculated for C? 9H22FN304S: C 56.01, H 5.44, N 10.31, S 7.87, Found: C 56.01, H 5.52, N 10.04, S 7.39. The starting material was prepared as follows: i) To a solution of 1- (4-fluorophenyl) piperazine (35 g, 194 mmol) and pyridine (17.5 ml) in dry dichloromethane (200 ml) at 0 ° C methanesulfonyl chloride was added (20 ml, 258 mmol) per drop. The mixture was stirred for 3 hours at room temperature. The mixture was washed with water and extracted with dichloromethane (2 x 100 ml). The organic layers were dried with MgSO and evaporated in vacuo. The residue was triturated and washed with methanol to give 1- (4-fluorophenyl) -4- (methanesulfonyl) piperazine (39.35 g) as white crystals. 2 H NMR (CDCl 3): 7.00 (m, 2H), 6.90 (m, 2H), 3.40- (m, 4H), 3.20 (m, 4H), 2.83 (s, 3H). ii) To a solution of LDA [4.5 mmoles; prepared by slowly adding n-butyllithium (3.5 ml, 8.5 mmol, 2.5 M in hexane) to a solution of diisopropylamine (860 mg, 8.5 mmol) in dry THF (5 ml) at -78 ° C] to -78 ° C a solution of 1- (4-fluorophenyl) -4- (methanesulfonyl) piperazine was added (1 g, 3.87 mmol) in THF (25 ml) per drop. The mixture was stirred at -78 ° C for 1 hour and a solution of diethylchlorophosphate (670 mg, 3.87 mmol) in THF (3 ml) was added. The mixture was stirred at -78 ° C for 1 hour and benzaldehyde (450 mg, 4.24 mmol) in THF (3 ml) was added. The mixture was gently warmed to room temperature and stirred for 18 hours. The mixture was washed with aqueous ammonium chloride and extracted with ethyl acetate. The organic layers were washed with water, brine and dried over MgSO4. Purification of the residue on silica (eluent: dichloromethane) yielded 1- (4-fluorophenyl) -4- (trans-β-styrenesulfonyl) -piperazine as a white powder (621 mg, 46%). X H NMR (CDC13): 7.50 (, 3 H), 7.43 (m, 3 H), 6.97 (m, 2 H), 6.89 (m, 2 H), 6.71 (d, 1 H, J-15.4 Hz), 3.37 (m, 4 H) ), 3.19 (m, 4H). iii) To a solution of 1- (4-fluoroenyl) -4- (trans-β-styrenesulfonyl) piperazine (620 mg, 1.79 mmol) in THF (20 ml) was added hydroxylamine (3 ml, 50% aqueous solution) . The mixture was stirred for 18 hours. The solvent was evaporated. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried over MgSO4 to give l- [2- (hydroxyamino) -2-phenylethanesulfonyl] -4- (4-fluorophenyl) piperazine (730 mg). X H NMR (CDCl 3): 7.4-7.1 (m, 5H), 6.97 (m, 2H), 6.87 (m, 2H), 5.95 (broad, 1H), 4.74 (s, 1H), 4.60 (dd, 1H, J = 4 Hz, J '= 8.8 Hz), 3.56 (dd, 1H, J = 8.8 Hz, J' = 14.3 Hz), 3.40 (m, 4H), 3.19 (dd, 1H, J = 4 Hz, J ' = 14.3 Hz), 3.12 (m, 4H). Example 2 The following compounds were obtained in a similar manner: Compound Data ; 498 EXAMPLE 3 N-Hydroxy-3- [4- (4-fluorophenyl) piperazin-l-sullyl] propionamide To a solution of N- (2,4-dimethoxybenzyloxy) -N- (2,4,6-trimethoxybenzyl) -3- [4- (4-fluorophenyl) piperazine-1-sulfonyl] propionamide (125 mg, 0.19 mmol) in dichloromethane (2 ml) triethylsilane was added. { 66 μl, 0.42 mmol) and trifluoroacetic acid (150 μl). The mixture was stirred at room temperature for 4 hours. The solvents were evaporated in vacuo. The residue was purified by chromatography on silica (eluent: dichloromethane, then ethyl acetate, then dichloromethane-10% MeOH) to give 35 mg of the title compound. X NMR (DMSO d-6 + CF3COOD): 7.16 (m, 4H), 3.36 (m, 6H), 3.25 (m, 4H), 2.45 (t, 2H, J = 7.4 Hz); MS (ESI): 332 (MN +), 354 (MNa +). The starting material was obtained as follows: i) A solution of 3-mercaptopropionic acid (20 g, 185 mmol) in acetic acid (150 ml) - water (30 ml) at 0 ° C was reacted with gaseous chlorine (preferably condensed at -78 ° C, 20 ml). After the chlorine has been distilled the solvents were evaporated in vacuo; toluene was added and evaporated to give 1,2-oxathiolan-5-one 2-dioxide (36.12 g). XHRMN (DMSO, d-6): 2.70 (t, 2H, J = 7.2 Hz), 2.50 (t, 2H, J = 7.2 Hz). ii) A solution of 1,2-oxathiolan-5-one 2-dioxide (3.8 g, 28 mmol) in thionyl chloride (20 ml) and DMF (5 drops) was stirred at room temperature for 18 hours. The mixture was heated at 40 ° C for 1 hour. The solvents evaporated; Toluene was added and evaporated in vacuo to give the crude 3-chlorosulfonylpropionyl chloride (NMR purity: 70%, 3.58 g). XH NMR (CDC13): 4.02 (t, 2H, J = 7.2 Hz), 3.63 (t, 2H, J = 7.2 Hz) iii) To a solution of 3-chlorosulfonylpropionyl chloride (500 mg, 1.83 mmol, 70% purity) and diisopropylethylamine (75 μl) in dichloromethane (5 ml) at -78 ° C was added a solution of O-dimethoxybenzyl-N-trimethoxybenzylhydroxylamine [Ref11 (664 mg, 1.83 mmol) and diisopropylethylamine (320 μl, 1.83 mmol) in dichloromethane (5 ml) by dripping for 2 hours. After 30 minutes, a solution of 1- (4-fluorophenyl) piperazine (330 mg, 1.83 mmol) and diisopropylethylamine (320 μL, 1.83 mmol) in dichloromethane (5 mL) was added to the reaction mixture. The solution was warmed to room temperature and stirred for 2 hours. The solution was divided between dichloromethane and IN hydrochloric acid. The organic layers were washed with brine and dried over MgSO4. Chromatography of the residue on silica gel (eluent: ethyl acetate - petroleum ether - gradient 50/50 to 80/20) gave N- (2, -dimethoxybenzyloxy) -N- (2,4,6-trimethoxybenzyl) -3- [4- (4-fluorophenyl) piperazine-1-sulfonyl] propionamide (260 mg). MS (El): 661 (M +) Example 4 N-hydroxy-3- [4-benzylpiperazin-1-sullyl] propionamide In a manner analogous to that described in Example 3, the title compound was obtained from 4-benzylpiperazine and 3-chlorosulfonylpropionyl chloride. X H NMR (DMSO d-6 + CF 3 COOD): 7.50 (m, 5 H), 4.41 (s, 2 H), 3.78 (m, 2 H), 3.41 (m, 4 H), 3.18 (m, 2 H), 2.43 (t, 2H, J = 7.1 Hz); MS (ESI); 328 (MH +). Example 5 N-Hydroxy-3- [4- (4-fluoro-enyl) piper-zin-1-sulfonyl] -2-isobutylpropionamide.
To a solution of N- (2,4-dimethoxybenzyloxy) -3- [4- (4-fluorophenyl) piperazine-1-sulfonyl] -2-isobutylpropionamide (220 mg) in dichloromethane (4 ml) was added trifluoroacetic acid (200 μl) and triethylsilane (145 μl). The mixture was stirred at room temperature for 15 minutes, evaporated) in vacuo and the residue was purified on silica gel (eluent: dichloromethane-ether-methanol (80: 20: 0.5) to dichloromethane-methanol (80:20) to Give the title compound (88 mg, 56%). 1 H NMR (DMSO d-6): 10.72 (s, 1H), 7.08 (m, 2H), 6.99 (m, 2H), 3.37 (dd, 1H J = 8.4 Hz, J '= 14.3 Hz), 3.27 (m, 4H), 3.15 (m, 4H), 3.00 (dd, 1H, J = 4 Hz, J' = 14.3 Hz), 2.62 (m, 1H), 1.6 -1.2 (m, 3H), 0.89 (d, 3H, J = 6.6 Hz), 0.85 (d, 3H, J = 6.6 Hz), MS (ESI): 388 (MH +), 410 (MNa +). The starting material was obtained as follows: i) A solution of 3-acetylthio-2-isobutylpropionic acid [obtained by Michael addition of thiolacetic acid in 2-isobutylacrylic acid] (7 g, 34.3 mmol) benzyl bromide (4.29 ml, 36 mmol) and DBU (5.2 ml, 35 mmol) in toluene (55 ml) was stirred for 18 hours at room temperature. The solvents were evaporated in vacuo. The residue was partitioned between ethyl acetate and 5% sodium bicarbonate. The organic layer was washed with brine and dried over MgSO4. Purification of the residue by chromatography on silica gel (eluent: dichloromethane-ether (9: 1)) gave benzyl 3-acetylthio-2-isobutylpropionate (8.4 g) MS (ESI): 317 (MNa +). ii) A solution of benzyl 3-acetylthio-2-butylpropionate (588 mg, 2 mmol) in acetic acid (12 ml) - water (1.6 ml) at 0 ° C was reacted with gaseous chloride (condensed preferably at -78 ° C, 1.9 ml). After the chlorine had been distilled, the solvents were evaporated in vacuo to give crude 3-chlorosulfonyl-2-isobutylpropionate benzyl (630 mg). MS (El): 318 (M +). iii) A solution of benzyl 3-chlorosulfonyl-2-isobutylpropionate (630 mg, 2 mmol), 1- (4-fluorobenzyl) piperazine (378 mg, 2.1 mmol) and triethylamine (340 μl, 2.4 mmol) in dichloromethane (15 ml) was stirred at 0 ° C for 18 hours. After evaporation of the solvents, the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over MgSO4. After evaporation of the solvent in vacuo, the residue was purified by chromatography on silica gel (eluent: dichloromethane-ether (9: 1) to give 3- [4- (4-fluorophenyl) piperazine-1-sulfonyl] -2 -benzyl isobutylpropionate (640 mg) EM (El): 462 (M +) iv) A solution of benzyl 3- [4- (4-fluorophenyl) piperazin-1-sulfonyl] -2-isobutylpropionate (630 mg) in methanol (10 ml) was hydrogenated under pressure 40 PSI for 18 hours in the presence of palladium on charcoal (63 mg, 10%). The catalyst was removed by filtration and the solvents were removed in vacuo to give 3- [4- (4-fluorophenyl) piperazine-1-sulfonyl] -2-isobutylpropionic acid (460 mg). MS (ESI): 373 (MH +), 395 (MNa +). v) To a solution of 3- [4- (4-fluorophenyl) piperazine-1-sulfonyl] -2-isobutylpropionic acid (230 mg, 0.62 mmol), 2,4-dimethoxybenzylhydroxylaminat Ref 1] (124 mg, 0.68 mmol), DMAP (75 mg, 0.62 mmol) in DMF (1 ml) was added N-ethyl-N '- (3-dimethylaminopropyl) -carbodiimide hydrochloride (152 mg, 0.8 mmol). The mixture was stirred at room temperature for 2 days. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 5% sodium bicarbonate, brine and dried over MgSO4. Purification of the residue on silica gel (eluent: dichloromethane-ether: gradient from 9/1 to 8/2) gave N- (2,4-dimethoxybenzyloxy) -3- [4- (4-fluorophenyl) -piperazine-1 -sulfonyl] -2-isobutylpropionamide (158 mg). XH NMR (CDC13): 8.21 (s, 1H), 7.30 (m, 1H), 6.97 (m, 2H), 6.88 (m, 2H), 6.46 (m; 2H), 4.95 (m, 2H), 3.82 ( s, 6H), 3.50 (dd, 1H, J = 9 Hz, J '= 14.2 Hz), 3.37 (m, 4H), 3.14 (m, 4H), 2.84 (dd, 1H, J = 14.2 Hz, J' = 2 Hz), 2.60 (m, 1H), 1.7-1.2 (m, 3H), 0.90 (m, 6H).
Example 6 4- [4- (4-fluorophenyl) piperazine-1-sulfonylmethyl] tetrahydro-pyran-4- (N-hydroxycarboxamide) To a solution of 4- [4- (4-fluorophenyl) piperazine-1-sulfonylmethyl] tetrahydropyran-4-carboxylic acid (470 mg, 1.21 mmol) in dichloromethane (8 ml) was added oxalyl chloride (700 mg, 5.6 mmol) ) and DMF (18 μl). The mixture was heated at 35 ° C for 1 hour. After evaporation of the solvents, the unpurified acid chloride was dissolved in dichloromethane (4 ml) was added to a solution cooled with hydroxylamine ice (440 μl, 50% aqueous solution) in THF (8 ml). The mixture was stirred for 90 minutes at room temperature. After evaporation of the solvents, the residue was triturated in dichloromethane-ether-methanol (80: 20: 5). The resulting solid was washed with water and ethyl acetate and dried to give the title compound as white crystals (230 mg, 47%). 1 NMR (DMS0 d-6): 10.56 (broad s, 1H), 8.74 (broad s, 1H), 7.07 (m, 2H), 6.99 (m, 2H), 3.66 (m, 2H), 3.47 (m, 2H), 3.40 (s, 2H), 3.25; (m, 4H), 3.16 (m, 4H), 1.99 (m, 2H), 1..72 (m, 2H); MS (ESI): 402 (MH +), 424 (MNa +).
The starting material was prepared as follows: (i) thioacetic acid (760 μl, 10 mmol) and tributylphosphine (2.5 ml, 10 mmol) in DMF (5 ml) was added dropwise to ice-cooled suspension of sodium hydride ( 530 mg, 60% in oil, 13 mmol) in DMF (1.5 ml) under an argon atmosphere. The mixture was stirred at 0 ° C for minutes. To the above solution was added 2,7-dioxaspiro [3, 5] nonan-l-one [Ref 21 (1.4 g, 10 mmol) in DMF (10 ml). The mixture was stirred at 0 ° C for 30 minutes and at room temperature for 18 hours. The reaction mixture was diluted with ether. The precipitate was filtered and dried to give sodium salt of 4- (acetylthiomethyl) tetrahydropyran-4-carboxylic acid. XH NMR (DMSO d-6): 3.65-3.40 (m, 4H), 2.99 (s, 2H), 2.27 (s, 3H), 1.86 (m, 2H), 1.23 (m, 2H). (ii) Using the same procedure described in Example 5 i), ii), iii), iv), v) except that no DBU was used in step 1, from the sodium salt of 4- (acetylthiomethyl) acid tetrahydropyran-4-carboxylic acid was obtained 4- [4- (4-fluorophenyl) piperazine-1-sulfoniomethyl] -tetrahydropyran-4-carboxylic acid (490 mg). 4- (acetylthiomethyl) tetrahydropyran-4- (carboxylic acid benzyl ester): MS (ESI): 331 (MNa +) 4- (chlorosulfonylmethyl) tetrahydropyran-4- (carboxylic acid benzyl ester): MS (ESI): 354 (MNa +); 4- [4- (4-fluorophenyl) piperazine-1-sulfonylmethyl] tetrahydropyran-4-carboxylic acid benzyl ester: MS (ESI): 477 (MH +), 499 (MNa +); 4- [4- (4-fluorophenyl) piperazine-1-sulfonylmethyl] tetrahydropyran-4-carboxylic acid: MS (ESI): 387 (MH +), 409 (MNa +). Ref 1: B. Barlaam, A. Hamon, M. Maudet; Tetrahedron Lett, 1998, 39, 7865 Ref 2: F. Hoffmann-La Roche, Agouron Pharm .; Eur. Patent Appl. EP 780386. Example 7 1- [2- (N-formyl-N-hydroxyamino) -2-phenylethanesulfonyl] -4-phenylpiperazine To a solution of 1- [2- (hydroxyamino) -2-phenylethanesulfonyl] -phenylpiperazine (140 mg) in THF (0.75 ml) and formic acid (0.25 ml) was added a pre-formed formic acid mixture (0.58 ml) and acetic anhydride (0.29 ml). The solution was stirred at room temperature for 18 hours. The mixture was evaporated in vacuo, diluted with dichloromethane and washed with saturated sodium bicarbonate solution, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 1% methanol in dichloromethane to give 1-phenyl- (4-trans-β-styrenesulfonyl) piperazine (420 mg) as a foam (105 mg). ^ • H NMR (d6-DMSO at 373K): 9.60 (s, 1H), 8.25 (s, 1H), 7.40 (m, 2H), 7.30 (m, 3H), 7.20 (m, 2H), 6.90 (d , 2H), 6.75 (m, 1H), 5.60 (m, 1H), 3.85 (dd, 1H), 3.60 (dd, 1H), 3.30 (m, 4H); 3.15 (m, 4H) m / z: 390 (M + 1). The starting material was prepared as follows: A solution of phenylpiperazine (487 mg) in dichloromethane (6 ml) containing triethylamine (0.63 ml) was added dropwise over 5 minutes to the trans-β-styrenesulfonyl chloride (638 g) in dichloromethane (4 ml). The solution was stirred at room temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 1% methanol in dichloromethane to give 1-phenyl- (4-trans-β-styrenesulfonyl) piperazine (420 mg) as a solid. XH NMR (d6-DMS0): 7.75 (m, 2H), 7.40 (m, 4H), 7.30 (d, 1H), 7.20 (dd, 2H), 6.90 (d, 2H), 6.80 (dd, 1H), 3.20 (s, 8H) m / z 329 (M + l). To a solution of 1-phenyl-4- (rans-b-styrenesulfonyl) piperazine (108 mg) in THF (3 mL) was added hydroxylamine (0.45 mL, 50% aqueous solution). The mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane, washed with water, dried (Na2SO4) and evaporated to give the product 1- [2- (hydroxyamino) -2-phenylethanesulfonyl] -4-phenylpiperazine as a foam (120 mq). 1 NMR (dß-DMSO): 7.50 (m, 1H), 7.40 (m, 2H), 7.30 (m, 5H), 6.90 (d, 2H), 6.80 (dd, 1H), 5.90 (m, 1H), 4.20 (m, 1H), 3.60 (dd, 1H), 3.40 (dd, 1H), 3.20 (m, 4H); 3.10 (m, 4H) m / z 362 (M + 1). Example 8 1- [2- (N-formyl-N-hydroxyamino) -2- (quinolin-4-yl) ethane-1-sulfonyl] -4- (4-fluorophenyl) piperazine To a suspension of 1- [2- (N-hydroxyamino) -2- (quinolin-4-yl) ethan-1-sulfonyl] -4- (4-fluorophenyl) piperazine (148 mg, 0.34 mmol) in THF (2 ml) -CH 2 Cl 2 (2 ml) was added 5-methyl-3-formyl-l, 3,4-thiadiazol-2 (3 H) -thione (1) (140 mg, 0.87 mmol). The mixture was stirred for 3 hours. After addition of methanol (2 ml) and silica (1 g), the mixture was stirred for 18 hours. The solids were filtered. The filtrates were washed with saturated NaHCO 3 and brine. Evaporation of the solvents followed by trituration in acetonitrile-CH2Cl2 gave the starting material (60 mg). Chromatography of the mother liquors with acetonitrile-CH2C12 (1: 1) gave the title compound (20 mg, 13%). XH-NMR (CDC13): 8.97 (m, 1H), 8.21 (m, 2H), 8.01 (s, 1H), 7.8-7.65 (m, 3H), 6.97 (m, 2H), 6.86 (m, 2H) , 5.66 (m, 1H), 3.55-3.1 (m, 10H); MS (ESI): 459 (MH +). The starting material was prepared from quinoline-4-carboxaldehyde and 1- (fluorophenyl) -4- (methanesulfonyl) piperazine in a manner similar to Example 1 ii-iii): 188 mg: MS (ESI): 431 (MH + ); HPLC tR (column TSKgel super ODS 2 mm 4.6 mm x 5 cm, methanol / water gradient 20 to 100% in 5 minutes, flow rate: 1.4 ml / min): 3.43 minutes (1) Yazawa, H.; Goto, S. Tetrahedron Lett. 1985, 26, 3703 Example 9 1- [1- (N-formyl-N-hydroxyamino) -1- (3,4-dichlorophenyl) pentan-2-sul onyl-4- (4-fluorophenyl) piperazine.
In a similar manner to Example 1, the syn and anti diastereomers of 1- [1- (N-hydroxyamino) -1- (3,4-dichlorophenyl) pentan-2-sulfonyl] -4- (4-fluorophenyl) piperazine were converted to the title compound (as 2 diastereoisomers): diastereoisomer 1 from less polar hydroxylamine: 36 mg, 70%; XH-NMR (CDC13): 8.45 and 8.10 (s, 1H), 7.6-7.2 (m, 3H), 7.0-6.8 (m, 2H), 5.96 and 5.18 (m, 1H), 3.8-3.4 (m, 5H) ), 2.9-3.15 (m, 4H), 2.0-1.0 (m, 4H), 0.88 and 0.76 (t, 3H, J = 7 Hz); MS (ESI): 540 (M. {35C1, 35C1.}. Na +), 542 (M. {37Cl, 35 Cl.}. Na +). - diastereomer 2 from more polar hydroxylamine: 49 mg, 63%; XH-NMR (CDC13): 8.28 and 8.13 (s, 1H), 7.6-7.2 (m, 3H), 7.0-6.85 (m, 2H), 5.54 and 5.02 (m, 1H), 3.45-3.9 (m, 5H) ), 3.15 (m, 4H), 1.7-1.2 (m, 4H), 0.76 (t, 3H, J = 7 Hz); MS (ESI): 540 (M. {35C1, 35C1.) Na +) 542 (M. {37C1, 35C1.) Na +): The starting material was prepared as follows: Similar to Example 1 i ), 1- (4-fluorophenyl) piperazine and 1-butanesulfonyl chloride gave 1- (4-fluorophenyl) -4- (butan-1-sulfonyl) piperazine (1.84 g); similarly to Example 1 ii), this was reacted with 3,4-dichlorobenzaldehyde to give 4- (4-fluorophenyl) -1- [1- (3,4-dichlorophenyl) pent-l-ene-2-sulfonyl ] piperazine as a mixture of Z / E isomers (330 mg, 22%): MS (ESI): 457 (M. {35C1, 35C1.} H +), 459 (M. {37C1, 35C1.}. H +); similarly to Example 1 iii) except that the mixture was refluxed for 3 days, it was converted to 1- [1- (N-hydroxyamino) -1- (3,4-dichlorophenyl) pentan-2-sulfonyl] -4- (4-fluorophenyl) piperazine as the syn and anti diastereomers. The less polar isomer (50 mg, 15%) (TLC: eluent EtOAc-CH2C12-petroleum ether (15-45-50); -RMN (CDC1): 7.53 (d, 1H, J = 2.2 Hz), 7.46 (d, 1H, J = 7.4 Hz), 7.27 (m, 1H), 6.97 (m, 2H), 6.88 (m, 2H), 4.63 (m, 1H), 3.55 (m, 4H), 3. 16 (m, 5H), 1.75 (m, 2H), 1.4 (m, 1H), 1.2 (m, 1H), 0.77 (t, 3H, J = 7.4 Hz). More polar isomer (76 mg, 23%); ^ -RN (CDC13): 7.52 (d, 1H, J = 2 Hz), 7.45 (d, 1H, J = 8 Hz), 7.27 (m, 1H), 6.99 (m, 2H), 6.89 (m, 2H) ), 4.42 (m, 1H), 3.55 (m, 4H), 3.41 (m, 1H), 3.14 (m, 4H), 1.6 (m, 2H), 1.25 (m, 2H), 0.76 (t, • 3H, J = 7.3 Hz). Example 10 Trans 1- [2- (N-formyl-N-hydroxyamino) cyclohexane-1-sulfonyl] -4- (4-fluorophenyl) -piperazine In a similar manner to Example 1, from the trans 1- [2- (N-hydroxyamino) cyclohexane-1-sulfonyl] -4- (4-fluorophenyl) -piperazine the title compound was obtained (68 mg, 23% ). 1 H-NMR (CDC13): 8.39 and 8.02 (s, 1H), 6.98 (m, 2H), 6.88 (m, 2H), 4.40 and 3.92 (m, 1H), 3.35-3.55 (m, 5H), 3.15 ( m, 4H), 2.35 (m, 1H), 2.0-1.8 (m, 3H), 1.2-1.6 (m, 4H); MS (ESI): 408 (MNa +). The starting material was obtained as follows: i) To a solution of LDA (51 mmol, prepared by slow addition of n-butyllithium (20.4 ml, 2.5 M in hexane, 51 mmol) to a solution of diisopropylamine (5.16 g) , 51 mmol) in THF (30 ml) at -78 ° C) at -78 ° C was added a solution of 1- (4-fluorophenyl) -4- (methanesulfonyl) -piperazine (6 g, 23.2 mmol) in THF (150 ml). The mixture was stirred for 1 hour at -78 ° C. A solution of 5-chlorovaleryl chloride (4 g, 25.8 mmol) in THF (20 ml) was added dropwise. The mixture was stirred at -78 ° C for 1 hour at room temperature for 18 hours. The solution was diluted with EtOAc and washed with saturated NH 4 Cl and brine and dried over MgSO 4. Chromatography of the residue on silica gel (eluent: EtOAc-CH2C12-petroleum ether (15:35:50) yielded 1- (6-chloro-2-hexanone-l-sulfonyl) -4- (4-fluorophenyl) piperazine (5.22 g, 60%) as white crystals: MS (ESI: 399 (MNa +)) ii) A mixture of this compound (5.22 g, 13.9 mmol) and Nal (42 g) in acetone (90 ml) was brought to reflux for 5 hours. After cooling and partition between EtOAc and water, the organic layer was washed with 10% NaHS03, and brine, and dried over MgSO4 to give l- (6-iodo-2-hexanone-1-sulfonyl) -4- ( 4-fluorophenyl) piperazine (6.13 g, quantitative) as yellowish crystals: 1 H-NMR (CDC 13): 6.98 (m, 2 H), 6.88 (m, 2 H), 4.00 (s, 2H), 3.46 (t, 4H, J = .8 Hz), 3.19 (t, 2H J = 6.6 Hz), 3.16 (t, 4H, J = 4.8 Hz), 2.79 (t, 2H, J = 6.6 Hz) , 1.85 (m, 2H), 1.74 (m, 2H). iii) A mixture of this compound (1.27 g, 4.85 mmol) and cesium carbonate (8 g, 24.5 mmol) in CH2C12 (90 mL) was stirred at room temperature for 4 hours. To the mixture, water and 2N HCl were slowly added until pH ~ 7. The mixture was extracted with CH2C12. The organic layer was dried over MgSO4. Chromatography on silica gel (eluent: EtOAc-petroleum ether (4: 6)) yielded 1- (cyclohexanone-2-sulfonyl) -4- (4-fluorophenyl) piperazine (880 mg, 53%). 1 H-NMR (CDC 13): 6.97 (m, 2 H), 6.88 (m, 2 H), 3.83 (m, 1 H), 3.48 (m, 4 H), 3.12 (m, 4 H), 2.81 (m, 1 H), 2.54 (m, 1H), 2.46 (m, 1H), 2.2-2.0 (m, 3H), 1.75 (m, 2H); MS (ESI): 363 (MNa +); IR: 1716. Additional elution (EtOAc-petroleum ether (6: 4)) yielded 1- [(tetrahydropyran-2-yl) methylidensufonyl] -4- (4-fluorophenyl) piperazine (630 mg, 38%): 1H -NRM (CDC13): 6.98 (m, 2H), 6.87 (m, 2H), 5.21 (s, 1H), 4.14 (t, 2H, J = 5.2 Hz), 3.32 (m, 4H), 3.15 (m, 4H), 2.35 (t, 2H, J = 6.6 Hz), 1.82 (m, 4H); MS (ESI): 363 (MNa +). iv) To a solution of 1- (cyclohexanone-2-sulfonyl) -4- (4-fluorophenyl) piperazine (284 mg, 0.83 mmol) in methanol-THF (16 ml 3: 1) at 0 ° C was added borohydride. sodium (3.7 mg, 1 mmol). The mixture was stirred at 0 ° C for 30 minutes and at room temperature for 1 hour 30. The solvents were evaporated. Saturated NH4C1 and water were added. The precipitate was filtered, washed with water and dried to give 1- (2-cyclohexanol-1-sulfonyl) -4- (4-fluorophenyl) piperazine (250 mg, 88%): MS (ESI): 343 (MH + ). v) To a solution of 1- (2-cyclohexanol-1-sulfonyl) -4- (4-fluorophenyl) piperazine (310 mg, 0.9 mmol) in THF (15 ml) was added triphenylphosphine (1.18 g, 4.5 mmol) and DEAD (712 μl, 4.5 mmol) per drop. The mixture was stirred at room temperature for 18 hours. Evaporation of the solvents and purification on silica gel (eluent: EtOAc-petroleum ether, gradient from 2: 8 to 3: 7) gave 1- [1-cyclohexen-1-sulfonyl] -4- (4-fluorophenyl) piperazine (285 mg, 98%): MS (ESI: 325 (MH +) vi) similar to Example iii) except that the reaction was heated at 65 ° C for 30 hours, from 1- (1-cyclohexen) -l-sulfonyl) -4- (4-fluorophenyl) piperazine (280 mg, 0.86 mg) trans 1- [2- (N-hydroxyamino) cyclohexane-1-sulfonyl] -4- (4-fluorophenyl) piperazine was obtained ( 270 mg, 88%) 1H-NMR (CDC13): 6.98 (m, 2H), 6.88 (m, 2H), 3.54 (m, 4H), 3.34 (m, 2H), 3.14 (m, 4H), 2.30 ( m, 1H), 2.17 (m, 1H), 2.05 (, 1H), 1.9-1.2 (m, 5H); MS (ESI): 358 (MH +). Example 11 Cis 1- [2- (N-formyl-N-hydroxyamino) cyclohexane-1-sulfonyl] -4- (4-luoro-enyl) piperazine In a similar manner to Example 1, from cis 1- [2-N (hydroxyamino) cyclohexane-1-sulfonyl] -A- (4-fluorophenyl) -piperazine the title compound was obtained (18 mg, 18%). H-NMR (CDC13): 8.39 and 8.07 (s, 1H), 6.98 (m, 2H), 6.88 (m, 2H), 4 77 and 4.25 (m, 1H), 3.48 (m, 5H), 3.13 (m , 4H), 2.25-1.3 (m, 8H); MS (ESI): 408 (MNa +). The starting material was obtained as follows: i) A mixture of 1- (cyclohexanon-2-sulfonyl) -4- (4-fluorophenyl) piperazine (50 mg, 0.14 mol), hydroxylamine hydrochloride (51 mg, 0.73 mmol) and potassium acetate (72 mg, 0.73 mmol) in methanol (5 ml) was heated at 70 ° C for 4 hours. The solvents evaporated. After they were partitioned between EtOAc and water, the organic layer was washed with brine and dried over MgSO4 to give l- [2- (N-hydroxyimino) cyclohexane-1-sulfonyl] -4- (4-fluorophenyl) piperazine as a solid. white (48 mg, 94%): MS (ESI): 356 (MH +). ii) To this compound (210 mg, 0.6 mmol) in a THF-acetic acid mixture (7 mL, 1: 1) was added sodium cyanoborohydride (276 mg, 4.4 mmol). The mixture was stirred at room temperature for 18 hours. The water was added and the pH adjusted to 9. The mixture was extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. Chromatography on silica (eluent: EtOAc-petroleum ether, gradient from 1: 1 to 8: 2), gave cis l- [2- (N-hydroxyamino) cyclohexane-1-sulfonyl] -4- (4-fluorophenyl) piperazine (97 mg, 45%). H-NMR (CDC13): 6.98 (m, 2H), 6.89 (m, 2H), 3.63 (m, 1H), 3.52 (m, 4H), 3.24 (dt, 1H ~ Jd = 10.6 Hz, Jt = 3.5 Hz ), 3.15 (m, 4H), 2.2-1.2 (m, 8H); MS (ESI): 358 (MH +). Example 12 The following compounds were made using the method set forth in Example 1: * = M-H R2 = hydrogen PIP = piperazinyl RH = reverse hydroxamate A = carboxylic acid Cl 7H24FN305S (M + H) cale.402, found 402. The aryl / heteroarylpiperazines and piperidines used as starting materials are commercially available and are described in the literature, for example 4- (4-fluorophenyl) -piperidine, CAS number 37656 -48-7 Piperazine, 1- [1,1 '-biphenyl] -4-yl- (180698-19-5) Piperazine, 1- [1,1' -biphenyl] -3-yl- (115761-61- 0) Piperazine, 1- (2-naphthalenyl) - (57536-91-1) Piperazinone, 1-phenyl- (90917-86-5) 1H-1,4-Diazepine, 1- (4-chlorophenyl) hexahydro- ( 41885-98-7) Quinoline, 4-methyl-2- (1-piperazinyl) - (50693.78-2) Piperazine, 1- (4-phenoxyphenyl) -62755-61-7 Piperazine, 1- (3-chlorophenyl) - The 2-methyl-4- (4-fluorophenyl) -piperazine used as a starting material was prepared as follows: Sodium t-butoxide (4.1 g) was added to a solution of tir-tolylphosphine (0.638 g) and palladium acetate (0.319 g) in toluene (250 L) under argon and the mixture was stirred for 20 minutes. 4-Fluoro-bromobenzene (5 g) and 2-methylpiperazine (2.85 g) were added and the mixture was heated at 110 ° C for 7 hours, then allowed to cool to room temperature and maintained at this temperature for 20 hours. The reaction mixture was filtered through Celite®, the filter cake was washed twice with dichloromethane (2X25 mL) and the filtrate was evaporated to dryness. The residue was chromatographed on silica eluting initially with dichloromethane and then with a mixture of dichloromethane, methanol and ammonium hydroxide (100: 5: 1) to give 2-methyl-4- (4-fluorophenyl) -piperazine, 2.5 g . Using the same method and 2,6-dimethylpiperazine as the starting material, 2,6-dimethyl-4- (4-fluorophenyl) -piperazine was obtained. Piperazine, 1- [1, 1 '-biphenyl-4'-fluoro] -4-yl Hydrochloride. Tert-butoxycarbonyl piperazine, 1- [1,1'-biphenyl-4'-fluoro] -4-yl (0.721 g) was stirred in a mixture of dichloromethane (10 ml) and trifluoroacetic acid (1.0 ml) for 18 hours at ambient temperature, evaporated in vacuo to a gray solid and used without further purification. The tert-butoxycarbonyl piperazine, 1- [1,1'-biphenyl-4'-fluoro] -4-yl used as starting material was prepared as follows: Sodium t-butoxide (1.35 g) was added to a solution of S- (-) -2, 2'-bis (diphenylphosphino) -1, 1'-biphenyl (0.046 g) and bis (dibenzylidene ketone) palladium (0.023 g) in toluene (25 ml) under argon and then added 4- bromo-4'-fluorobiphenyl (2.51 g) and 1-tert-butoxycarbonylpiperazine (2.2 g) and the mixture was heated at 80 ° C for 5 hours. The reaction mixture was filtered, the filtrate was evaporated in vacuo to a yellow solid which was triturated and then filtered from diethyl ether (20 ml) to give tert-butoxycarbonyl piperazine, 1- [1,1'-biphenyl] -4 '-fluoro] -4-yl, (2.67 g), mp 165-166 ° C. NMR (d6-DMSO) 1.42 (s, 9H), 3.15 (m, 4H), 3.48 (m, 4H), 7.02 (d, 2H), 7.22 (m, 2H), 7.51 (d, 2H), 7.63 ( m, 2H); m / z 357 (M + l). Example 13 Acetic anhydride (0.23 ml) was added directly to formic acid (0.9 ml). The solution was stirred at room temperature for 30 minutes and then a solution of N- [2-. { [4- (6-chlorpyrimidin-4-yl) tetrahydropyrazin-1-yl] -sulfonyl} -1- (3, -dichlorophenyl) ethyl] hydroxylamine (0.227 g) in tetrahydrofuran (5 ml). The solution was stirred at room temperature for 18 hours. The solution was evaporated (water bath at a temperature of 30 ° C) and the residual gum was purified through chromatography using 10 g of silica isolate eluting with CH2C12-3% Methanol / CH2C12 to give N [2-. { [4- (6-chloropyrimidin-4-yl) piperazino] sulfonyl} -l- (3,4-dichlorophenyl) ethyl] -N-hydroxyformamide (0.178 g), 98-101 ° C. NMR (d6-DMS0 373 ° K): 3.31 (m, 4H), 3.70 (dd, 1H), 3.75 (m, 4H), 3.95 (dd, 1H), 5.61 (broad vs. 1H), 6.89 (s, 1H), 7.43 (dd, 1H), 7.60 (d, 1H), 7.70 (d, 1H), 8.29 (s, 1H), 36 (s, 1H); m / z 4 94 (M + l] Acetic anhydride (0.63 ml) was added directly to formic acid (2.48 ml). The solution was stirred at room temperature for 30 minutes and then a solution of N- [2-. { [4- (5-chloropyridin-2-yl) piperazino] sulfonyl} -l- (3, 4-dichlorophenyl) ethyl] hydroxylamine (0.61 g) in tetrahydrofuran (10 ml). The solution was stirred at room temperature for 3 hours and then diluted with ethyl acetate, neutralized with pH with saturated aqueous sodium hydrogen carbon solution. The ethyl acetate layer was separated, dried (Na2SO4), and evaporated to dryness. The residue was purified by chromatography using a silica isolate eluting with 10% ethyl acetate / hexane-80% ethyl acetate / hexane and then evaporated to dryness. The resulting white solid was filtered from diethylether to give [2-. { [4- (5-chloropyridin-2-yl) piperazino] sulfonyl} -l- (3,4-dichlorophenyl) ethyl] -N-hydroxyformamide (0.431 g), 211-212 ° C. NMR (d6-DMS0 373 ° K): 3.30 (m, 4H), 3.80 (m, 4H), 3.85 (dd, 1H), 3.95 (dd, 1H), 5.58 (broad vs. 1H), 6.85 (d, 1H), 7.43 (m, 1H), 7.58 (m, 2H), 7.85 (d, 1H), 8.10 (d, 1H), 8.13 (s, 1H); m / z 493 (M + l).
Acetic anhydride (0.48 ml) was added directly to formic acid (1.9 ml). The solution was stirred at room temperature for 30 minutes and then a solution of N- (2- (benzyloxy) -l- { [(4-pyridin-2-ylpiperazino) sulfonyl] methyl.} Ethyl) hydroxylamine was added. (0.42 g) in tetrahydrofuran (5 ml). The solution was stirred at room temperature for 3 hours and then diluted with ethyl acetate, neutralizing the pH with saturated aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was separated, dried (Na2SO4), and evaporated. to dryness The residue was purified by chromatography using a 10 g silica isolate eluting with CH2C125% Methanol / CH2C12 to give N- (2- (benzyloxy) -l- { [(4-pyridin-2-ylpiperazino) sulfonyl] methyl-ethyl) -N-hydroxyformamide (0.233 g), 70-75 ° C. NMR (d6-DMS0 373 ° K): 3.25 (dd, 1H), 3.31 (m, 4H), 3.48 (dd, 1H), 3.65 (m, 4H),, 3.66 (dd, 1H), 3.70 (dd, 1H), 4.55 (broad vs 1H), 4.55 (s, 2H), 6.70 (m, 1H), 6.85 (d, 1H), 7.28 (m, H), 7.32 (m, 4H), 7.58 (m, 1H), 8.17 (m, 2H), 9.45 (broad s, 1H); m / z 435 (M + l).
Acetic anhydride (0.48 ml) was added directly to formic acid (1.9 ml). The solution was stirred at room temperature for 30 minutes and then a solution of N- (3-pyridin-2-yl-l-. {[[(4-pyridin-2-ylpiperazino) sulfonyl] -methyl-propyl) was added. hydroxylamine (0.152 g) in tetrahydrofuran (5 ml). The solution was stirred at room temperature for 3 hours and then diluted with ethyl acetate, neutralized to pH with saturated acid sodium carbonate solution. The ethyl acetate layer was separated, dried (Na2SO4), and evaporated to dryness The residue was purified by chromatography using 10 g of silica isolated eluting with CH2C125% Methanol / CH2C12 to give N-hydroxy-N - (3-pyridin-2-yl-l- { [(4-pyridin-2-ylpiperazino) sulfonyl] -methyl} propyl) formamide (0.039 g), 80-84 ° C NMR (d6-DMS0 373 ° K): 2.10 (m, 2H), 2.80 (m, 2H), 3. 25 (dd, 1H), 3.30 (m, 4H), 3.50 (dd, 1H), 3.60 (m, 4H), 4.42 (broad vs. 1H), 6.70 (m, 1H), 6.85 (d, 1H), 7.19 (m, 1H), 7.22 (d, 1H), 7.54 (m, 1H), 7.65 (m, 1H), 8.10 (broad vs. 1H), 8.15 (m, 1H), 8.45 (m, 1H), 9.50 (broad broad, 1H); m / z 420 (M + l).
Example 14 N-. { 1- [( { 4- [(5-chloropyridin-2-yl) oxy] piperidino.] Sulfonyl) methyl] -3-pyridin-3-ylpropyl} -N-hydroxyformamide To a solution of 1-N- [2- (hydroxyamino) -2- (3-pyridinyl) butanesulfonyl] -4-0- (5-chloro-2-pyridinyl) piperidine (2.1 g, 4.18 mmole) in THF (36 ml) was added a mixture of formic acid (9.0 ml) and acetic anhydride (2.25 ml). The mixture was stirred at room temperature for 18 hours. The reaction was neutralized using saturated aqueous NaHCO3 before extracting the solution with EtOAc (x2). The combined organics were dried over Na 2 SO 4 and evaporated in vacuo. The residue was stirred in MeOH at room temperature for 20 hours to remove the bis-formyl. The residue was crystallized from EtOH to yield a white solid (0.898 g). P.f. 130-140 ° C. X NMR (DMSO-100 ° C): 9.50 (broad s, 1H), 8.43 (d, 1H), 8.39 (dd, 1H), 8.15 (d, 1H), 8.13 (broad s, 1H), 7.74 (dd) , 1H), 7.60 (m, 1H), 7.27 (m, 1H), 6.83 (d, 1H), 5.12 (m, 1H), 4.32 (s broad, 1H), 3.42 (m, 3H), 3.16 (m , 3H), 2.68-2.54 (m, 2H), 2.06-1.93 '(m, 4H), 1.76 (m, 2H); MS (ES +): 469.2 (MH +), 491.1 (MNa +); EA: calculated for C20H25C1N405S: C 51.22, H 5.37, CI 7.56, N 11.95, S 6.84, Found: C 50.92, H 5:30, Cl 7.55, N 11.90, S 6.75. The starting material was prepared as follows: i) NaH (2.88 g, 66 mmol, 55% dispersion in mineral oil) was stirred in dry DME (200 ml) under Argon. A mixture of 2,4-dichloropyridine (8.87 g, 60 mmol) and 4-hydroxypiperidine (6.67 g, 66 mmol) dissolved in dry DME (200 ml) was added to the NaH suspension by drip, over a period of 30 minutes . After the addition was complete, the reaction was heated at 82 ° C for 48 hours, maintaining the argon blanket. The reaction was quenched slowly with water before removing most of the THF. The aqueous was extracted with DCM (x3). The organic layers were dried with Na 2 SO and evaporated in vacuo to yield 2- (4-piperidinyloxy) -5-chloropyridine as a yellow oil (12.7 g, quantitative). 2 H NMR (DMSO): 8.17 (d, 1H), 7. 76 (dd, 1H), 6.81 (d, 1H), 4.96 (m, 1H), 2.93 (m, 2H), 2.53 (m, 2H), 1.91 (m, 2H), 1.46 (m, 2H); MS (ES +); 213.3 (MH +), 225.3 (MNa +) ii) To a solution of 2- (4-piperidinyloxy) -5-chloropyridine (12.9 g, 0.06 mol) and Et3N (25.4 mL, 0.182 mol) in dry dichloromethane (400 mL) at 0 ° C and under Argon, methanesulfonyl chloride (5.3 ml, 0.067 mol) in dry dichloromethane (100 ml) was added dropwise. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with dichloromethane (250 ml), then washed with water (x3) then brine. The organic layers were dried on Na2SO4 and evaporated in vacuo. The residue was triturated and washed with diethyl ether to give 2- (N-methanesulfonyl-4-piperidinyloxy) -5-chloropyridine (15.1 g) as a pale yellow solid. 1 H NMR (DMSO): 8.20 (d, 1H), 7.81 (dd, 1H), 6.87 (d, 1H), 5.09 (m, 1H), 3.32 (m, 2H), 3.11 (m, 2H), 2.90 ( s, 3H), 2.02 (m, 2H), 1.75 (m, 2H); MS (ES +): 291.2 (MH +), 313.2 (MNa +). iii) 2- (N-methanesulfonyl-4-piperidinyloxy) -5-chloropyridine (2.0 g, 6.89 mmol) was taken in anhydrous THF (100 ml) under Argon, then cooled to -78 ° C before the addition of Li (TMSA) (13.8 ml of a l.OM solution of THF, 13.8 mmol). The mixture was stirred at -78 ° C for 20 minutes and a solution of diethylchlorophosphate (1.05 ml, 7.23 mols) was added. The mixture was stirred at -78 ° C for 1 hour before 3-pyridinylpropanal (1.12 g, 8.27 mmol) was added, then stirred at -78 ° for an additional 1 hour. The mixture was allowed to warm to room temperature, then washed with aqueous ammonium chloride and extracted with ethyl acetate. The organic layers were washed with water, brine and dried over Na2SO4. Purification of the residue on silica (eluent: gradient, DCM-2% MeOH / DCM) yielded 2-. { N- [E / Z-4 (3-pyridyl) -but-lenyl] sulfonyl} 4-piperidinyloxy) -5-chloropyridine as a yellow oil (2.09 g). 1 H NMR (DMSO): 8.45 (m, 1H), 8.37 (m, 1H); 8.19 (m, 1H), 7.82 (m, 1H), 7.64 (m, 1H,), 7.30 (ml 1H), 6.85 (, 1H), 6. 88-6.27 (m, 2H, E / Z isomers), 5.00 (m, 1H), 3.15 (m, 2H), 2. 83 (m, 5H), 2.61 (m, 1H), 1.85 (m, 2H), 1.70 (m, 2H); EM (ES +): 408.1 (MH +), 430.2 (MNa +). iv) To a solution of 2-. { N- [E / Z-4 (3-pyridyl) -but-lenyl] sulfonyl} 4-piperidinyloxy) -5-chloropyridine (2.09 g, 5.1 mmol) in THF (20 ml) was added hydroxylamine (3.4 ml, 50% aqueous solution). The mixture was stirred for 18 hours. The solvent was evaporated. The residue was dissolved in EtOAc and washed with water (x4). The organic layer was dried over Na 2 SO and evaporated in vacuo to give 2- (4-piperidinyloxy) -5-chloropyridine 1-N- [2- (hydroxyamino) -2- (3-pyridinyl) -butansulfonyl] -4-0 - (5-chloro-2-pyridinyl) piperidine (730 mg). X H NMR (DMSO): 8.43 (d, 1H), 8.37 (dd, 1H), 8.18 (d, 1H), 7.78 (dd, 1H), 7.61 (m, 1H), 7.36 (s, 1.1), 7.29 ( m, 1H), 7.85 (d, 1H), 5.70 (s, 1H), 5.08 (m, 1H), 3.35 (m, 3H), 3.16-3.00 (broad m, 4H), 2.80-2.60 (broad m, 2H), 1.98 (m, 2H), 1.84 (m, 2H), 1.69 (m, 2H); MS (ES +): 441.2 (MH +), 463.2 (MNa +). Using an analogous procedure to that described in Example X, an aryl-4-O-piperidine was reacted with the appropriate aldehyde to give the compounds listed in the following: The following aryl-4-O-piperidines have been previously described: Piperidine, 4- (3-chlorophenoxy) - (9C1) CAS (97840-40- ') Piperidine, 4- (4-chlorophenoxy) - (9C1), CAS (97839-99-i; Piperidine, 2- (4-piperidinyloxy) - (9C1), CAS (127806-46-6) Piperidine, 4- (3,4-dichlorophenoxy) - (9C1) was synthesized in the following alternative route. 1) To a stirred solution of 4-hydroxypiperidine (3.5 g, 0.035 mole) in dry methanol (50 ml) at 0 ° C, di-butyl dicarbonate (9.2 ml, 0.042 mole) in dry methanol (50 ml) was added dropwise. The mixture was stirred for 20 hours at room temperature. The methanol was removed and the resulting solution was taken in Et20, then washed with citric acid ÍM (x3) and water (x3). The combined aqueous extracts were extracted with Et20 which was dried with NaSO4 and evaporated in vacuo. Purification of the residue on silica (eluent: gradient, DCM-30% MOH / DCM) yielded N-B0C-4-hydroxypiperidine as a yellow oil (6.4 g). X NMR (DMSO): 4.05 (, 2H), 3. 70-3.52 (broad m, 3H), 2.92 (m, 2H), 1.66 (, 2H), 1.40 (s, 9H), 1.33-1.18 (broad m, 2H); MS (ES +): 201.3 (MH +), 219. 4 (MNH4 +). 2) To a stirred solution of N-BOC-4-hydroxypiperidine (2.0 g, 0.01 mol), triphenylphosphine (3.68 g, 0.014 mol) and 3,4-dichlorophenol (1.96 g, 0.012 mol) in dry toluene (75 ml) [with molecular sieves, a 0 ° C and under Argon] diethyl azodicarboxylate was added (2.52 ml, 0.016 moles) per drip. The mixture was stirred for 1.5 hours at 0 ° C. The solution was filtered and the toluene was removed before vigorously stirring isohexane "(100 ml) and the resulting suspension was filtered.The filtrate was quenched with 2M aqueous NaOH (x8), dried with Na2SO4 and evaporated in vacuo. residue on silica (eluent: 20% EtOAc / isohexane) yielded N-Boc-Piperidine, 4- (3,4-dichlorofepoxy) - (9C1) as a yellow solid (1.96 g) XH NMR (DMSO): 7.52 ( d, 1H), 7.31 (d, 1H), 7.01 (dd, 1H), 4.62 (m, 1H), 3.65 (m, 2H), 3.15 (m, 2H), 1.88 (m, 2H), 1.53 (m , 2H), 1.40 (s, 9H), MS (ES +): 346.3 (MH +), 368.4 (MNa +). 3) 50% aqueous trifluoroacetic acid (18 ml) was added to a stirred solution of N-Boc-piperidine. 4- (3,4-dichlorophenoxy) - (9C1) (1.96 g, 5.66 mmoles) After 3.5 hours, toluene was added and evaporated in vacuo, this was repeated twice, then the residue was taken up in EtOAc, it was washed with saturated aqueous NaHCO3 (x3), dried with Na2SO and evaporated in vacuo to yield piperidine, 4- (3,4-dichlorophenoxy) - (9C1) a white solid (1.3 g). X NMR (DMSO): 7.54 (d, 1H), 7.35 (d, 1H), 7.04 (dd, 1H), 4.70 (m, 1H), 3.31 (m, 2H), 3.09 (m, 2H), 2.08 ( m, 2H), 1. * 80 (m, 2H); MS (ES +): 2.26.3 (MH +). Piperidine, 4- (3, -dichlorophenoxy) - (9C1) was then taken through steps ii-iv as described above.
Example 15 1-Mesyl-4- (5-methoxycarbonyl-2-pyridyl) piperazine 1-Methylpiperazine hydrochloride (4.24 g) was added to a solution of methyl 6-chloronicotinate (1.7 g) and N, N-diisopropylethylamine (6.3 ml) in dimethylacetamide (20 ml) and the mixture was heated at 120 ° C for 2 hours. The mixture was allowed to cool to room temperature and was poured into crushed ice / water (50 ml) to precipitate a stannous solid. The solid was collected by filtration and dried at 80 ° C for 18 hours in a vacuum oven to give l-mesyl-4- (5-methoxycarbonyl-2-pyridyl) piperazine (2.05 g), m.p. 205-207 ° C. NMR (dd-DMSO): 2.90 (s, 3H), 3.20 (m, 4H), 3.78 (m, 3H), 3.80. (s, 3H), 6.92 (d, 1H), 8.00 (dd, 1H), 8.67 (d, 1H); m / z 300 (M + l). Using an analogous procedure, 1-raesylpiperazine hydrochloride, CAS (161357-89-7), was reacted with appropriate chloropyridine to give the following compounds: 1- (6-chloropyrimidin-4-yl) -4-mesylpiperazine A mixture of 4,6-dichloropyrimidine (39.4 g), 1-mesylpiperazine hydrochloride (55.7 g) and triethylamine (116 ml) in ethanol (500 ml) are stirred at reflux temperature for 4 hours. The mixture was then stirred at room temperature for 12 hours. The solid, which had separated, was collected by filtration, the suspension was washed with ethanol (2 × 80 ml, 160 ml) then with diethyl ether (150 ml), and dried to give 1- (6-chloropyrimidin-4-yl). ) -4-mesylpiperizine as a cream-colored solid (71.9 g), mp 200-202 ° C. NMR (d6-DMS0): 2.88 (s, 3 H), 3.18 (m, 4 H), 3.80 (m, 4 H), 7.04 (s, 1 H), 8.38 (m, 1 H); m / z 277.3 (M + l). Using an analogous procedure, the 1-mesylpiperazine hydrochloride, CAS (161357-9-7), was reacted with the appropriate chloropyrimidine or chloropyridazine to give the following compounds.
Example 16 Acetic anhydride (19 ml) was added directly to formic acid (76 ml). The solution was stirred at room temperature for 30 minutes. A solution of 1- (6-chloropyrimidin-4-yl) -4-. { [2- (hydroxyamino) -4-phenylbutyl] -sulfonyljpiperazine (17.2 g) in tetrahydrofuran (85 ml) was added in portions to the above solution at 27 ° C for 25 minutes. The solution was stirred at room temperature for 1 hour. The solution was evaporated (water bath at a temperature of 30 ° C) and the residual gum was dissolved in ethyl acetate (500 ml). This solution was treated with saturated aqueous sodium hydrogen carbonate solution (200 ml) and the mixture (pH8) was stirred at room temperature for 16 hours. The ethyl acetate layer was separated, washed with saturated brine (100 ml), dried (Na2SO) and evaporated to dryness. The residual foam was dissolved in ethanol, a separate solid and the mixture was stirred for 2 days. The solid was collected by filtration, the suspension was washed with diethylether (100 ml) and dried to give N- [1- ( { [4- (6-chloropyrimidin-4-yl) piperazino] sulfonyl} methyl. ) -3-phenylpropyl] -N-hydroxyformamide as a colorless solid (12.8 g), m.p. 155-157 ° C. Found C, 50.29, H, 5.29, Cl, 7.82, N, 15.31, and S, 6.82%. C1H24C1N50 S required C, 50.27, T, 5.33, Cl, 7.81, N, 15.43, and S, 7.06%. NMR (d6-DMS0 373 ° K): 1.93 (m, 1H), 2.03 (m, 1H), 2. 57 (m, 1H), 2.65 (m, 1H), 3.20 (dd, 1H), 3.26 (t, 4H), 3.48 (dd, 1H), 3.74 (t, 4H), 4.3 (broad v, 1H), 6.90 (s, 1H), 7.19 (m, 3H), 7.27 (m, 2H), 8.1 (broad, 1H), 8.38 (s, 1H), 9.5 (s, 1H); m / z 454.2 (M + l).
Acetic anhydride (31.5 ml) was added directly to formic acid (126 ml). The solution was stirred at room temperature for 30 minutes. A solution of 1-. { [3-benzyloxy-2- (hydroxyamino) propyl] sulfonyl} 4- (6-chloropyrimidin-4-yl) pi-perazine (29.5 g) in tetrahydrofuran (150 ml) and formic acid (25 ml) was added in portions to the above solution at 25 ° C for 25 minutes. The solution was stirred at room temperature for 1 hour. The solution was evaporated (water bath at 3 ° C temperature) and the residual gum was dissolved in ethyl acetate (500 ml). This solution was treated with saturated aqueous sodium hydrogen carbonate solution (2x250 ml) and the mixture (pH8) was stirred at room temperature for 16 hours. The ethyl acetate layer was separated, washed with saturated brine (100 ml), dried (Na 2 SO 4) and evaporated to dryness. The residual foam was dissolved in methanol (70 ml) and the solution was stirred for 16 hours. The solution was evaporated to dryness (water bath at a temperature of 30 ° C). The residual foam was stirred in ethanol (250 ml), the solid was separated and the mixture was stirred for 18 hours. The solid was collected by filtration, the suspension was washed with diethyl ether (100 ml) and dried to give N- [2- (benzyloxy) -1- ( { [4- (6-chloropyrimidin-4-yl) piperazino ] sulfo-nyl.} methyl) ethyl] -N-hydroxyformamide (25.5 g). P.f. 118-120 ° C. Found C, 48.35, H, 5.09. Cl, 7.26", N, 14.73, and S, 6.78%, Ci9H24ClN5? 5S required C, 48.56, H, 5.15, Cl, 7.54, N, 14.90, and S, 6.82%. NMR (d6-DMS0 373 ° K) : 3.23 (dd, 1H), 3.30 (t, 4H), 3.46 (dd, 1H), 3.57 (dd, 1H), 3.67 (dd, 1H), 3.72 (t, 4H), 4.50 (s, 2H), 4.50 (m, 1H), 7.35 (m, 5H), 8.15 (broad, 1H), 8.38 (s, 1H), 9.48 (broad, 1H), m / z 470.2 (M + l).
Acetic anhydride (0.8 ml) was added directly to formic acid (3.2 ml). The solution was stirred at room temperature for 30 minutes. A solution of 1- (5-chloro-2-pyridyl) -4-. { [2- (hydroxyamino) -4-phenylbutyl] sulfonyljpiperazine (0.72 g) in tetrahydrofuran (5 ml) was added to the above solution at room temperature. The solution was stirred at room temperature for 2 days. The solution was evaporated (water bath at a temperature of 40 ° C). The residue was dissolved in methanol in 5% dichloromethane. Silica (5g of Merck 9385) was added to the solution, the mixture was stirred for 21 hours, and evaporated to dryness. The material (pre-adsorbed on silica) was purified by chromatography on silica (Bond Elut 10 g), using 0-3% methanol in dichloromethane as eluent to give N- [1- ( { [4- (5- chloro-2-pyridyl) piperazino] sulfonyl.] methyl) -3-phenylpropyl] -N-hydroxyformamide as an orange foam (0.17 g). NMR (d6-DMS0 373 ° K): 1.92 (m, 1H), 2.04 (m, 1H), 2.55 (m, 1H), 2.64 (m, 1H), 3.20 (dd, 1H), 3.27 (m, 4H ), 3.47 (dd, 1H), 3.58 (m, 4H), 4.35 (broad v, 1H), 6.88 (dd, 1H), 7.17 (m, 3H), 7.27 (m, 2H), 7.57 (dd, 1H), 8.10 (s, 1H), 8.10 (broad, 1H), 9.5 (s, 1H); m / z 453.3 (M + l). Example 17 To formic acid (31.5 ml) acetic anhydride (7.9 ml) was added. After 20 minutes it was added to the hydroxylamine (6.10 g) it was dissolved in THF (80 ml) and formic acid (40 ml) and the resulting solution was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in DCM (500 ml), washed with saturated sodium bicarbonate solution (2x500 ml), dried and evaporated to dryness. To the residue was dissolved in DCM (10 ml) diethyl ether (100 ml) was added to give the product as a white solid (5.60 g) which was collected by filtration. P.f. 168-170 ° C. NMR DMSOd6 d 10.2 (broad s, 1H) *; 9.8 (s broad, 1H) *; 8.7 (broad s, 1H) *; 8.6 (s broad, 1H) *; 8.5 (d, 1H); 8.3 (m, 1H); 8.1 (d, 1H); 7.9-7.8 (m, 1H); 7.6 (dd, 1H); 7.4 (dd, 1H); 6.9 (d, 1H); 5.8 (m, 1H) *; 5.5 (m, 1H) *; 4.1-3.6 (m, 2H); 3.6 (m, 4H); 3 ~ .2 (m, 4H). Analysis Calculated for C? 7H2oClN504S; C, 48.0; H, 4.7; Cl, 8.3, N, 16.5; S, 7.5. Found: C, 47.9; H, 4.7; Cl, 8.4; N, 16.3; S, 7.5. MS for C? 7H2oClN504S (M + H) calculated 426, found 426. ^ rotary signals Stage A d) The oxime (31.05 g) [Tetrahedron Letters 1994, 3_5, 1011] was dissolved in DCM (500 ml) and 3-pyridinecarboxaldehyde (12.09 g) was then added by anhydrous magnesium sulfate (13.6 g). After 2 days of stirring at room temperature more magnesium sulfate (13.6 g) was added and the stirring was continued for 3 additional days. The mixture was then filtered, the solvent was evaporated and the residue was triturated with diethylether to give the product (36.34 g) as a white solid. P.f. 174-175 ° C. NMR CDC13 d 9.0 (s, 1 H); 8.9 (d, 1H); 8.7 (d, 1H); 7.7 (s, 1H); 7.4 (dd, 1H); 5.6 (s, 1H); 5.3 (d, 1H); 4.9 (dd, 1H); 4.6 (dd, 1H); 4.4 (ddd 1H); 4.2 (dd, 1H); 3.7 (dd, 1H); 1.5 (s, 3H); 1.4 (s, 3H); 1.4 (s, 3H); 1.3 (s, 3H). Stage B di (2) Methylsulfonamide (14.30 g) was dissolved in THF (500 ml) and cooled to -10 ° C when lithium hexamethyldisilazide (78 ml, l.OM in THF) was added. After 30 minutes the solution was cooled to -78 ° C and the nitrone (18.00 g) was dissolved in THF (35U ml) was added, keeping the temperature low -65 ° C. The resulting solution was stirred for 3 hours at -78 ° C when it was quenched by the addition of brine (500 ml) and the aqueous layer was extracted with ethyl acetate (3 × 500 ml). The combined organic layers were dried and evaporated to give a yellow solid which was triturated with ethyl acetate / isohexane (4: 1) and then purified by flash column chromatography eluting with dichloromethane / methanol (97: 3) give 1 (16.40 g) as a white solid. P.f. 209-211 ° C (decomposition). NMR CDC13 d 8.6 (s, 1H); 8.4 (d, 1H); 8.1 (d, 1H); 7.8 (d, 1H); 7.5 (broad s, 1H); 7.4 (dd, 1H); 7.3 (dd, 1H); 6.6 (d, 1H); 4.9 (d, 1H); 4.8 (s, 1H); 4.7-4.6 (m, 2H); 4.2-4.1 (m, 3H); 3.8 (dd, 1H); 3.6 (dd, 1H); 3.5-3.4 (m, 5H); 3.3-3.2 (m, 4H); 1.4 (s, 3H); 1.3 (s, 3H); 1.3 (s, 3H); 1. 3 (s, 3H). Stage C (2. 3) To a solution of hydroxylamine 2 (14.90 g) in ethanol (300 ml) was added water (220 ml) followed by O-benzylhydroxylamine hydrochloride (13.91 g) and sodium bicarbonate (6.95 g). The heating gave a solution which was stirred overnight at 80 ° C. The ethanol was removed under reduced pressure and the residue was separated between water (500 ml) and ethyl acetate (500 ml). The aqueous layer was washed with ethyl acetate (2x500 ml) and the combined organic layers were dried and evaporated to give a residue which was triturated with dichloromethanes (100 ml) to give 3 (6.10 g) as a white solid. The mother liquor was purified by column chromatography eluting with ethyl acetate followed by dichloromethane / methanol (96: 4) to give additional 3 (0.85 g). P.f. 170-173 ° C. NMR DMS0d6 d 8.6 (s, 1H); 8.5 (d, 1H); 8.1 (d, 1H); 7.8 (d, 1H); 7.6 (dd, 1H); 7.6 (s, 1H); 7.3 (dd, 1H); 6.9 (d, 1H); 6.1 (broad s, 1H); 4.3 (broad s, 1H); 3.7-3.4 (m, 6H); 3.2-3.1 (m, 4H). Example 18 The following compounds were made using the method set forth in Example 7 * = M-H R2 = hydrogen PIP = piperazinyl RH = reverse hydroxamate The starting material was prepared as follows: The addition of hydroxylamine to 1-trans-β-styrenesulfonyl-piperidin-4- (N-phenylcarboxamide) and the subsequent formylation of the product was carried out as described in Example 7. Dimethylformamide (2 drops) was added to a suspension of 1-trans-β-styrenesulfonyl-piperidine-4-carboxylic acid (0.75 g) and oxalyl chloride (0.23 mL) in dichloromethane (10 mL) and stirred for 2 hours. The reaction mixture was evaporated to dryness, redissolved in dichloromethane (10 L) and evaporated to dryness again. The residue obtained was dissolved in dichloromethane (4 mL) and a mixture of aniline (0.23 mL) and triethylamine (0.35 mL) was added dropwise. The mixture was stirred for 20 hours and washed with dilute 2M hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and water and dried. Removal of the solvent gave 1-trans-β-styrenesulfonyl-piperidin-4- (N-phenylcarboxamide), 0.89 g. Using the method described above, the following 1-trans-β-styrenesulfonyl-piperidine-4-carboxamides were prepared A solution of ethyl piperidin-4-carboxylate (3.99 g) in a mixture of THF (30 mL) and methanol (6 mL) was treated with aqueous sodium hydroxide solution (20 mL) of 2M NaOH) and the mixture was stirred. stirred for 3 hours, evaporated to small volume and acidified to pH 5 with dilute 2M hydrochloric acid. The obtained mixture was extracted with ethyl acetate (2x25 mL), the ethyl acetate extracts were washed with water, dried and evaporated to dryness to give l-trans-β-styrenesulfonyl-piperidin-4-carboxylic acid, 2.64 g. A solution of ethyl piperidine-4-carboxylate (3.0 mL) and triethylamine (2.7 mL) in dichloromethane (10 mL) was added dropwise to a cooled solution (ice bath) of trans-β-styrenesulfonyl chloride (3.95 g) in dichloromethane (10 mL). The reaction mixture was allowed to warm to room temperature and stirring was continued for 20 hours. The reaction mixture was evaporated to dryness, the residue was diluted with water and extracted with ethyl acetate. (2x25 mL). The combined ethyl acetate extracts were washed with brine and dried (MgSO 4) to give ethyl 1- (trans-β-trans-β-styrenesulfonyl) -piperidine-4-carboxylate 5.76 g, M + H = 324. - An alternative procedure of the preparation of l-trans-β-3, dichloroestirenesulfonyl-piperidine-4-carboxylic acid was used: To a solution of 1-trans-β-3, 4-dichlorosterenesulfonicloride (2.7 g) and isonipecotic acid (1.41 g) ) in acetonitrile (15 ml) was added 2M sodium hydroxide (11 ml) and stirred at room temperature for 1 hour. The reaction mixture was acidified to pH 3 with 2M hydrochloric acid and extracted with ethyl acetate (2x15 ml), the ethyl acetate extracts were dried (Na 2 SO), adjusted and evaporated to give 1-trans-β -3, 4-dichloro-styrene-sulfonyl-piperidine-4-carboxylate (2.67 g) m / z 364 (M + 1). Example 19 The following compounds were prepared PIP = piperazinyl Z = reverse hydroxamate group R2 = hydrogen Example 20 NMR data were provided for the following compounds: (DMSO) 9.6 (1H, s), 8.5 (1H, m), 8.4 and 7.9 (1H, s), 7. 7 (1H, m), 7.2 (2H, m), 7.1 (2H, m), 7.0 (2H, m), 4.7 and 4.2 (1H, broad m), 3.4 (1H, m), 3.3 (5H, m), 3.1 (4H, m), 2.7 (2H, m), 2.1 (2H, m).
(DMSO) 9.8 and 9.5 (1H, broad s), 8.3 and 8.0 (1H, s), 8.1 (1H, d), 7.6 (1H, dd), 7.2 (5H, m), 6.9 (1H, d) ), 4.7 and 4.1 (1H m broad), 3.6 (4H, m), 3.4 (1H, m), 3.3 (1H, m), 3.2 (4H, m), 2.6 (2H, m), 1.6 (4H, m).
(DMSO) 9.6 (1H, broad S), 8.4 (1H, m), 8.3 and 7.9 (1H, s), 8.1 (1H, d), 7.6 (2H, m), 7.2 (1H, d), 7.1 (1H, m), 6. 9 (1H, d), 4.7 and 4.1 (1H, broad m), 3.6 (4H, m), 3.4 (1H, m), 3.3 (1H, m), 3.2 (4H, m), 2.7 (2H, m ), 2.0 (2H, m).
(DMSO) 9.7 (1H, broad), 8.5 (1H, m), 8.4 (1H, m), 8.1 and 7.9 (1H, s), 7.6 (1H, m), 7.2 (2H, m), 7.0 ( 1H, m), 4.6 and 4.1 (1H, broad m), 3.7 (4H, m), 3.4 (1H, m), 3.3 (5H,), 2.7 (2H, m), 2.0 (2H, m).
(DMSO) 9.9 (1H, s), 8.4 (2H, m), 8.2 (1H, d), 7.65 (2H, m), 7.3 (1H, m), 7.0 (1H, m), 4.0-4.2 (2H , m), 3.6 (4H, broad m), 3.4-3.2 (6H, broad m), 2.0 (2H, broad m).
: DMSO) 10.0 (1H, s), 8.5 (2H, d), 8.2 (1H, broad), 7.8 (1H, broad), 7.6 (1H, m), 7.4 (1H, m), 6.9 (1H, m), 3.6 (4H, broad m), 3.2 (6H, broad m). . 0 (1H, s), 8.5 (2H, m), 8.4 and 8.0 (1H, s), 7.9 (1H, m), 7.7 (1H, m), 7.3 (1H, m), 7.1 (1H, m) , 3.7 (4H, broad m), 3.45 (2H, m), 3.3 (4H, broad m), 2.75 (3H, m), 2.1 (2H, m).
(DMSO) 10.0 (1H, broad), 8.6 (2H, m), 8.2 (1H, d), 7.2 (1H, m), 6.9 (4H, m), 4.9 and 4.2 (1H, broad), 3.4 ( 6H, m), 3.0 (6H, m), 1.9 (4H, m).
(DMSO) 9.8 (1H, broad), 8.7 (2H, m), 8.3 and 7.9 (1H, s), 8.1 (2H, s), 7.6 (1H, m), 7.3 (1H, m), 6.9 (1H , m), 4.1 (1H, broad m), 3.6 (4H, m), 3.2 (6H, m), 2.8 (2H, m), 1.8 (4H, m).
(CDC13) 8.5 (1H, m), 8.1 (2H, s), 8.5 and 8.0 (1H, s), 7.8 (1H, m), 7.4 (1H, m), 7.3 (2H, m), 6.6 (1H , m), 4 .8 and 4.2 (1H, broad m), 3.6 (4H, m) 3.2 (6H, m), 2.8 (2H, m), 1.8 (4H, m).
(DMSO) 8.5 (1H, d), 8.4 and 8.2 (1H, s), 7.7 (1H, m), 7.2 (6H, m), 4.8 and 4.2 (1H, broad m), 3.6 (4H, m), 3.2 (6H, m), 2.8 (2H, m), 1.8 (4H, m). Example 21 The following compounds were prepared PIP = piperazinyl Z = reverse hydroxamate group R2 = hydrogen All compounds were prepared as in Example 1, except those where ring A is 4-0 piperidinyl, which were prepared as in Example 14. Example 22 NMR data were provided for the following compounds listed in Example 21: M452587 - new compound RNM (DMSO) 9.9.9.6 (broad IHs); 8.6 (2H m); 8.3 and 7.9 (IH s); 8.1 (lH, dd); 7.3 (lH, m) 6.9 (lH, d); 4.7 and 4.2 (l Full, m); 3.6 (4H, m); 3.4-3.2 (6H, m); 2.8 (2H, m); 2.1 d),, 7.3 and 2.9 Example 23 Preparation of: Formic acid (4.8 L) was added at 0 ° C acetic anhydride (1.2 L). After 20 minutes it was added to hydroxylamine 2 (0.68 g), dissolved in THF (11 mL) and formic acid (5 mL) and the resulting solution was std overnight at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in DCM (100 mL), washed with saturated sodium bicarbonate solution (2x100 mL), dried (MgSO) and evaporated to dryness. The residue was purified by flash column chromatography eluting with dichloromethane / methanol (96: 4) to give the product (0.41 g) as a gum. NMR CDC13 5 9.7 (broad s, 1H) *; 9.2 (broad s, 1H) *; 8.4 (s, 1H) *; 8.0 (s, 1H) *; 7.5-7.2 (m, 5H); 7.0-6.8 (m, 4H); 5.7 (m, 1H) *; 5.4 (m, 1H) *; 3.9-3.4 (m, 5H); 3.3 (m, 1H) *; 3.2-2.9 (m, 4H); 2.8 (m, 1H) *. MS for C20H22FN3O3 (M + H) calculated 372, found 372. * rotary signals Stage A To 1- (4-fluorophenyl) piperazine (1.00 g) was dissolved in DCM (10 ml), cinnamoyl chloride (0.85 g) in DCM (10 ml) was added followed by triethylamine (1.55 ml). The solution was std at room temperature overnight. This was separated between DCM (150 ml) and water (100 ml), the organic layer was then washed with water (100 ml), dried (MgSO) and evaporated to dryness to give a cxeia-colored solid which was triturated with diethylether. (10 ml) to give 1 (1.20 g) as a white solid. NMR CDC13 d 7.7 (d, 1H); 7.5 (m, 2H); 7.4 (m, 3H); 7. 0-6.9 (m, 5H); 4.0-3.8 (m, 4H); 3.1 (m, 4H). EM for Ci9H19FN20 (M + H) calculated 311, found 311. Step B 1 To the amide (2.00 g) was dissolved in THF (40 ml) hydroxylamine (1 ml, 50% aqueous solution) was added. The solution was std at room temperature for 48 hours. The solvent was then evaporated under reduced pressure, toluene (50 ml) was added and this was also evaporated under reduced pressure. The residue was triturated with dichloromethane / methanol (98: 2) and the mother liquor was purified by flash column chromatography eluting with dichloromethane / methanol (98: 2) to give 2 (0.70 g) as a gum. NMR CDC13 5 7.5-7.2 (m, 5H); 7.0-6.9 (m, 2H); 6.9-6.8 (m, 2H); 4.5 (dd, 1H); 3.8-3.7 (m, 2H); 3.6-3.5 (m, 2H); 3.1-2.8 (m, 5H); 2.7 (dd, 1H). MS for C? 9H22FN302 (M + H) calculated 344, found 344.

Claims (14)

  1. CLAIMS 1. A compound of formula I characterized in that ring B is a monocyclic or bicyclic, aryl, aralkyl, heteroaryl or heteroaralkyl ring, comprising up to 12 ring atoms and containing one or more heteroatoms independently chosen from N, 0 and S; alternatively the ring B can be biphenyl; ring B may optionally be linked to ring A by an alkyl chain of Cl-4 or of alkoxy of Cl-4 linking the position 2 of ring B with an atom of carbon alpha to X2; each R3 independently is selected from hydrogen, halogen, N02, COOR wherein R is hydrogen or Cl-6 alkyl, CN, CF3 Cl-6 alkyl, -S-Cl-6 alkyl, -SO- alkyl C1-6, -S02-C1-6 alkyl, Cl-6 alkoxy and up to CIO aryloxy, n is 1, 2 or 3; P is - (CH) n- where n = 0, 1, 2 or P is an alkene or alkyne chain of up to six carbon atoms; where X2 is C; P can be -Het-, - (CH [R6]) n-Het-, -Het- (CH [R6] n- or -Het- (CH [R6] n-Het-, where Het is selected to start of -CO-, -S-, SO-, -S02-, -NR6-, or -O- wherein n is 1 or 2, or P can be selected from -C0-N (R6) -, - N (R6) -C0, -S02-N (R6) - and -N (R6) -S02-, and R6 is hydrogen, Cl-6 alkyl, up to C10 aralkyl or up to C9 heteroaryl; Ring A is a 5-7 membered aliphatic ring and may optionally be mono- or di-substituted by optionally substituted Cl-6 alkyl or Cl-6 alkoxy, each substituent being independently selected from halogen, Cl-6 alkyl or a oxo group XI and X2 are independently selected from N and C, wherein a ring substituent or ring A is an oxo group that is preferably adjacent to a ring of nitrogen atom; Y is selected from -S02 - and -CO-; Z is -CONHOH, Y is -CO- and Q is selected from -C (R6) (R7) -, -C (R6) (R7) -CH2-, N (R6) - , and -N (R6) -CH2- where R 6 is as defined above, and only in relation to Q as defined herein, R6 may also represent up to one CIO aryl and up to a C9 heteroaryl, and R7 is H, Cl-6 alkyl, or together with R6 forms a ring of 5, 6 or 7 spiro carbocyclic or heterocyclic members, the latter containing at least one heteroatom selected from N, O and S;
  2. Z is -CONHOH, Y is -S02- and Q is selected from -C (R6) (R7) - and -C (R6) (R7) -CH2-; 0 Z is -N (OH) CHO and Q is selected from
  3. -CH (R6) -, -CH (R6) -CH2-, and -N (R6) -CH2-; R1 is H, Cl-6 alkyl, C5-7 cycloalkyl, up to CIO aryl, up to CIO heteroaryl, up to C12 aralkyl, or up to C12 heteroarylalkyl, all optionally substituted by up to three independently selected groups of N02, CF3 , halogen, Cl alkyl, carboxylalkyl of (Cl-4), up to C6 cycloalkyl, -0R4,
  4. SR 4, Cl 4 alkyl substituted with -OR 4, SR 4 (and its oxidized analogs), NR 4, NY-R 4, or C 1-4 alkyl-Y-NR 4, with the proviso that when R 1 is -OH, -OR 4 , -SR 4 or NR 4, or NY-R 4 then Z is not -N (OH) CHO, or R 1 is 2,3,4,5,6-pentafluorophenyl; R4 is hydrogen, Cl-6 alkyl, up to CIO aryl or up to CIO heteroaryl or up to C9 aralkyl, each optionally independently substituted by halogen, N02, CN, CF3, Cl-6 alkyl, -S- Cl-6 alkyl, -SO-alkyl of Cl-6, -S02-Cl-6 alkyl or Cl-6 alkoxy; R 2 is H, Cl-6 alkyl, or together with R 1 forms a ring of 5, 6 or 7 spiro carboxylic or heterocyclic members, the latter containing at least one heteroatom selected from N, 0, and S; also the group Q may be linked to either R1 or R2 to form a ring of 5, 6, or 7 alkyl or heteroalkyl members, comprising one or more of 0, S and N; and wherein any of the alkyl groups set forth above may be straight or branched chain, or a pharmaceutically acceptable salt or hydrolysable precursor thereof in vivo. 2. A compound according to claim 1, and characterized in that: ring A is a 5-6 membered aliphatic ring, and may optionally be mono- or di-substituted by optionally substituted Cl-6 alkyl or Cl alkoxy -6, each substituent being independently selected from halogen, Cl-6 alkyl or an oxo group; - R3 is hydrogen, halogen, N02, * CF3", Cl4 alkyl, and Cl4 alkoxy, n is 1 or 2, ring B is monocyclic or bicyclic aryl, aralkyl or heteroaryl having up to 10 atoms in the ring, P is - (CH2) n- where n is 0 or 1, or -0-, or
  5. -C0-N (R6) -; one or both of X2 and XI = N, or XI is N, or X2 is C; Rl is hydrogen, Cl-6 alkyl, C5-7 cycloalkyl, up to C12 aralkyl, up to Cll heteroaryl, up to CIO aryl- or CIO heteroaryl; all optionally substituted up to three halogen atoms, or by CF3; R 2 is hydrogen, or together with R 1 represents a ring of 5 or 6 spiro carbocyclic or heterocyclic members; R4 is up to CIO aryl optionally substituted by halogen, N02, CN, CF3, Cl-6 alkyl, S-Cl-6 alkyl, -SO-Cl-6 alkyl, -S02-Cl-6 alkyl or Cl-6 alkoxy, or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof 3. The compound according to claim 1, characterized in that: R3 is hydrogen, halogen, N02, CF3, methyl, ethyl, methoxy or ethoxy ring B is a monocyclic, aralkyl or heteroaryl aryl ring having up to 7 ring atoms, P is a direct bond, both X2 and XI are N, Y is -S02-, Q is -CH2-, R1 is phenyl , 4-trifluoromethylphenyl, phenethyl, phenpropyl, isobutyl, cyclopentyl, benzyloxymethyl, 3,4-dichlorophenyl, 2-pyridyl, 3-pyridyl, 2-pyridylethyl, 3-pyridylethyl, thiophenylpropyl, bromothiophenyl, 2-pyrimidinylethyl, 2-pyrimidinylpropyl, pyridylpropyl or in conjunction with R2 is spirocyclohexane or spiro-4-pyran, R2 is hydrogen Z is -N (OH) CHO, or a pharmaceutically acceptable salt or hydrolysable precursor in vivo thereof. The compound according to any of the previous claims, characterized in that ring A is a piperazinyl ring and ring B is selected from an optionally substituted phenyl, pyridyl ring or pyrimidine or a pharmaceutically acceptable salt, or hydrolysable precursor in I live from it 5. The compound of formula I according to claim 1, characterized in that the ring B substituted by R3 (n) is a phenyl ring, 3-methylphenyl, 4-fluoraphenyl, 3-chlorosphenyl, 4-chlorophenyl, or 3, 4-di-chloroenyl or 5-chloro-2-pyridyl; P is a direct link; ring A is piperidinyl or piperazinyl; Y is S02, Q is -CH2- and Z is -N (OH) CHO; or a pharmaceutically acceptable salt or hydrolysable precursor thereof in vivo.
  6. 6. The compound of formula I according to claim 1, characterized in that ring B is a phenyl ring, 3-methyl phenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl or 3,4-dichlorophenyl or 5-chloro -2-pyridyl; P is a direct link; ring A is piperidinyl or piperazinyl, Y is S02, Q is -CH2-, Z is -N (OH) CHO and R1 is phenylbutylene, phenyisopropylene, 2-pyridylethylene, 2-pyridylisopropylene, 3-pyridylisopropylene, 4-pyridylisopropylene, or 4-chlorophenyloxydimethylmethylene; or a pharmaceutically acceptable salt or hydrolysable precursor thereof in vivo.
  7. 7. The compound of formula I according to claim 1, characterized in that ring B is phenyl or monosubstituted by chlorine or fluorine, P is a direct bond; ring A is piperidinyl, Y is S02, Q is -CH2-, Z is -CONHOH and R1 is hydrogen, i-butyl, or spiro-tetrahydropyranyl; or a pharmaceutically acceptable salt or hydrolysable precursor thereof in vivo.
  8. 8. The pharmaceutical composition which is characterized in that it comprises a compound of the formula (I) according to claim 1, or a pharmaceutically acceptable salt or a hydrolysable ester in vivo and a pharmaceutically acceptable carrier.
  9. 9. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or hydrolysable ester thereof, for use in a method of therapeutic treatment of the human or animal body.
  10. 10. A method for treating a metalloproteinase-mediated disease condition which is characterized in that it comprises administering to a warm-blooded animal a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or hydrolysable ester in vivo thereof. .
  11. 11. A process for preparing a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, which process is characterized in that it comprises a) reacting a compound of the formula (II) or a pharmaceutically salt acceptable or in vivo hydrolysable ester thereof with a compound of the formula (III) wherein Xi represents X or a precursor of X (either by modification or displacement) or an activated form of X suitable for the reaction with Yi; Yi represents Y, a precursor of Y, or an activated form of Y suitable for the reaction with Xi1; Z1 represents a protected form of Z, a precursor of Z (either by modification or displacement of Z1) or an activated form of Z; and where Q is - (CH2) (R6) - then a compound of the formula IX is reacted with an appropriate compound of the formula R1-CO-R2 to produce an alkene of the formula X, which is then converted to a compound of formula XI, wherein Z * is a hydroxylamine precursor of group Z, and then Z * is converted to group Z, all as stated below: IX b) reacting a compound of the formula (IV) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof with a compound of the formula (V). V wherein B1 represents a suitable ring function or substituent group to react with P1; Z1 is as defined above; and P1 represents a suitably activated form of the linker P to react with B1 O where X2 is N, then Pl may be present in ring A instead of ring B or, as required, linker P may be formed by appropriate reaction of the precursor groups P "and P" ', provided in rings B1 and A respectively, or vice versa.
  12. 12. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or hydrolysable precursor thereof in vivo thereof, in the preparation of a medicament for use in a disease condition mediated by one or more metalloproteinase enzymes.
  13. 13. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof in the preparation of a medicament for use in the treatment of arthritis. .
  14. 14. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or hydrolysable precursor thereof in vivo, in the preparation of a medicament for use in the treatment of atherosclerosis.
MXPA01001847A 1998-08-31 1999-08-25 Arylpiperazines and their use as metalloproteinase inhibiting agents (mmp). MXPA01001847A (en)

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Families Citing this family (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU773967B2 (en) * 1999-06-04 2004-06-10 Astrazeneca Ab Inhibitors of metalloproteinases
KR20020079882A (en) * 2000-02-21 2002-10-19 아스트라제네카 아베 Arylpiperazines and Arylpiperidines and Their Use as Metalloproteinase Inhibiting Agents
WO2001062750A1 (en) * 2000-02-21 2001-08-30 Astrazeneca Ab Arylpiperazines and their use as metalloproteinase inhibiting agents (mmp)
CA2396965C (en) * 2000-02-21 2010-03-16 Astrazeneca Ab Piperidine- and piperazine substituted n-hydroxyformamides as inhibitors of metalloproteinases
AU5499401A (en) * 2000-05-15 2001-11-26 Darwin Discovery Limited Hydroxamic and carboxylic acid derivatives having mmp and tnf inhibitory activity
US6469020B2 (en) 2000-05-15 2002-10-22 Darwin Discovery, Ltd. Hydroxamic and carboxylic acid derivatives
WO2001090100A1 (en) * 2000-05-25 2001-11-29 Smithkline Beecham P.L.C. Bicyclyl or heterobicyclylmethanesulfonylamino-substituted n-hydroxyformamides
SE0100902D0 (en) 2001-03-15 2001-03-15 Astrazeneca Ab Compounds
BR0210733A (en) 2001-07-02 2004-07-20 Astrazeneca Ab Useful piperidine derivatives useful as modulators of chemokine receptor activity
GB0119473D0 (en) * 2001-08-09 2001-10-03 Astrazeneca Compounds
GB0119472D0 (en) * 2001-08-09 2001-10-03 Astrazeneca Ab Compounds
GB0119474D0 (en) 2001-08-09 2001-10-03 Astrazeneca Ab Compounds
GB0120461D0 (en) 2001-08-22 2001-10-17 Astrazeneca Ab Novel compounds
WO2003022801A1 (en) 2001-09-07 2003-03-20 Kaken Pharmaceutical Co., Ltd. Reverse hydroxamic acid derivatives
GB0122503D0 (en) 2001-09-18 2001-11-07 Astrazeneca Ab Chemical compounds
WO2003040103A1 (en) * 2001-11-02 2003-05-15 Bristol-Myers Squibb Company β-SULFONE DERIVATIVES AS INHIBITORS OF MATRIX METALLOPROTEINASES AND/OR TNF-α CONVERTING ENZYME (TACE)
SE0103710D0 (en) 2001-11-07 2001-11-07 Astrazeneca Ab Compounds
TW200303304A (en) * 2002-02-18 2003-09-01 Astrazeneca Ab Chemical compounds
SE0200843D0 (en) 2002-03-19 2002-03-19 Astrazeneca Ab Chemical compounds
SE0200844D0 (en) 2002-03-19 2002-03-19 Astrazeneca Ab Chemical compounds
ES2309313T3 (en) 2002-04-03 2008-12-16 Topotarget Uk Limited CARBAMIC ACID COMPOUNDS THAT INCLUDE A COUPLING OF PIPERACINE AS HDAC INHIBITORS.
GB0216379D0 (en) * 2002-07-13 2002-08-21 Astrazeneca Ab Compounds
GB0216383D0 (en) * 2002-07-13 2002-08-21 Astrazeneca Ab Compounds
GB0216382D0 (en) * 2002-07-13 2002-08-21 Astrazeneca Ab Compounds
SE0202539D0 (en) 2002-08-27 2002-08-27 Astrazeneca Ab Compounds
GB0221250D0 (en) * 2002-09-13 2002-10-23 Astrazeneca Ab Compounds
US7465719B2 (en) 2003-01-17 2008-12-16 Topotarget Uk Limited Carbamic acid compounds comprising an ester or ketone linkage as HDAC inhibitors
SE0300957D0 (en) 2003-04-01 2003-04-01 Astrazeneca Ab Chemical compounds
WO2004113312A1 (en) * 2003-06-19 2004-12-29 Celltech R & D Limited Hydroxamate sulfonamides as cd23 shedding inhibitors
SE0301922D0 (en) * 2003-06-27 2003-06-27 Astrazeneca Ab Novel compounds
SE0400208D0 (en) 2004-02-02 2004-02-02 Astrazeneca Ab Chemical compounds
US7648992B2 (en) 2004-07-05 2010-01-19 Astrazeneca Ab Hydantoin derivatives for the treatment of obstructive airway diseases
GB0427403D0 (en) 2004-12-15 2005-01-19 Astrazeneca Ab Novel compounds I
SE0403086D0 (en) 2004-12-17 2004-12-17 Astrazeneca Ab Compounds
SE0403085D0 (en) 2004-12-17 2004-12-17 Astrazeneca Ab Novel componds
PL1828160T3 (en) * 2004-12-21 2012-02-29 Merck Serono Sa Sulfonyl amino cyclic derivatives and use thereof as mmp inhibitors
FR2885615B1 (en) * 2005-05-12 2007-06-22 Servier Lab NOVEL PHENYLPYRIDINYLPIPERAZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
FR2885616B1 (en) * 2005-05-12 2007-06-22 Servier Lab NOVEL PHENYLPYRIDINYLPIPERAZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
RU2008105987A (en) 2005-07-21 2009-08-27 Астразенека Аб (Se) NEW PIPERIDINE DERIVATIVES
EA013907B1 (en) * 2005-10-26 2010-08-30 Мерк Сероно С.А. Sulfonamide derivatives and use thereof for the modulation of metalloproteinases
JP5199109B2 (en) * 2005-11-24 2013-05-15 メルク セローノ ソシエテ アノニム N-hydroxyamide derivatives and uses thereof
SI1976828T1 (en) 2005-12-29 2017-07-31 Celtaxsys, Inc. Diamine derivatives as inhibitors of leukotriene a4 hydrolase
HUE030114T2 (en) 2010-07-08 2017-04-28 Kaken Pharma Co Ltd N-hydroxyformamide derivative and pharmaceutical containing same
JP6360500B2 (en) 2013-02-06 2018-07-18 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ Substituted carboxylic acid derivatives as aggrecanase inhibitors for the treatment of osteoarthritis
EP2968359B1 (en) 2013-03-12 2021-01-20 Celltaxis, LLC Methods of inhibiting leukotriene a4 hydrolase
EP2968265A4 (en) 2013-03-14 2016-12-28 Celtaxsys Inc Inhibitors of leukotriene a4 hydrolase
EP2970309A4 (en) 2013-03-14 2016-11-09 Celtaxsys Inc Inhibitors of leukotriene a4 hydrolase
EP2968264A4 (en) 2013-03-14 2016-11-02 Celtaxsys Inc Inhibitors of leukotriene a4 hydrolase
AU2019278935A1 (en) 2018-05-31 2020-12-10 Celltaxis, Llc Method of reducing pulmonary exacerbations in respiratory disease patients
CN112236424B (en) 2018-06-07 2024-03-15 爱杜西亚药品有限公司 Alkoxy-substituted pyridinyl derivatives
US20210393632A1 (en) 2018-10-04 2021-12-23 INSERM (Institut National de la Santé et de la Recherche Médicale) Egfr inhibitors for treating keratodermas

Family Cites Families (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3532340A (en) * 1967-08-11 1970-10-06 Vincent Nardiello Spring type abdominal exercising device
ES426195A1 (en) * 1973-05-18 1976-07-01 Mega Produc U Verpackungsentwi Weighted muscle exerciser
US4480831A (en) * 1982-03-12 1984-11-06 Mueller Deinhardt Friedhelm Exercise hoop having a counter
BE897714A (en) * 1983-09-09 1984-01-02 Nelissen Koenraad RING WITH ELASTIC AND HANDLE
US4724827A (en) * 1985-01-10 1988-02-16 Schenck Robert R Dynamic traction device
US4607625A (en) * 1985-01-10 1986-08-26 Schenck Robert R Dynamic traction device
GB9411598D0 (en) * 1994-06-09 1994-08-03 Hoffmann La Roche Hydroxamic acid derivatives
US5674162A (en) * 1995-06-07 1997-10-07 Ellingson; Richard L. Biomechanical stabilizer apparatus and methods for strengthening unstable joints and improving muscle coordination
DK0968182T3 (en) * 1996-08-07 2004-08-16 Darwin Discovery Ltd Hydroxamic and carboxylic acid derivatives with MMP and TNF inhibitory activity
AU743901B2 (en) * 1996-10-16 2002-02-07 Wyeth Holdings Corporation Ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloprote inase and tace inhibitors
WO1998027069A1 (en) * 1996-12-17 1998-06-25 Fujisawa Pharmaceutical Co., Ltd. Piperazine compounds as inhibitors of mmp or tnf
ZA98376B (en) 1997-01-23 1998-07-23 Hoffmann La Roche Sulfamide-metalloprotease inhibitors
US6376506B1 (en) 1997-01-23 2002-04-23 Syntex (U.S.A.) Llc Sulfamide-metalloprotease inhibitors
PL334846A1 (en) * 1997-01-23 2000-03-27 Hoffmann La Roche Sulphamidic inhibitors of metaloproteases
US6482827B1 (en) 1997-07-10 2002-11-19 Pharmacia & Upjohn S.P.A. Matrix metalloproteinase inhibitors
WO1999002510A1 (en) * 1997-07-10 1999-01-21 Pharmacia & Upjohn S.P.A. Matrix metalloproteinase inhibitors
WO1999006436A1 (en) * 1997-07-31 1999-02-11 Elan Pharmaceuticals, Inc. Benzyl compounds which inhibit leukocyte adhesion mediated by vla-4
US6294573B1 (en) 1997-08-06 2001-09-25 Abbott Laboratories Reverse hydroxamate inhibitors of matrix metalloproteinases
US6235786B1 (en) 1997-08-06 2001-05-22 Abbott Laboratories Reverse hydroxamate inhibitors of matrix metalloproteinases
US6130220A (en) 1997-10-16 2000-10-10 Syntex (Usa) Inc. Sulfamide-metalloprotease inhibitors
AU735929B2 (en) 1998-01-30 2001-07-19 Darwin Discovery Limited Hydroxamic and carboxylic acid derivatives
US6429213B1 (en) * 1998-06-17 2002-08-06 Bristol Myers Squibb Pharma Co Cyclic hydroxamic acids as metalloproteinase inhibitors
WO2000012477A1 (en) * 1998-08-29 2000-03-09 British Biotech Pharmaceuticals Limited Hydroxamic acid derivatives as proteinase inhibitors

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